Breast cancer in Vitamin D's Point of View

Vitamin D is a fat-soluble secosteroids found in small amount in few foods, including salmon, mackerel, sardines and tuna. The vitamin plays an important role in modulation of cellular proliferation, apoptosis induction, tumor growth suppression and promotion in absorption of minerals, including calcium, iron, magnesium, phosphate and zinc.

Levels of free circulation of vitamin are correlated with risk of Breast cancer
Epidemiologocal studies linking levels of free circulation of vitamin D correlated to the risk of breast cancer with inconsistent results. It may be due to age of subjects, menstrual stage, race,  etc.. Suggestions of levels of plasma 25-hydroxyvitamin D (25(OH)D)  in a breast cancer risk differentiation by menopause, showed an inversed association beyond a threshold of 27 ng/mL, but with flattening of effects above 35 ng/mL(1)and low levels of 25(OH)D  are at higher risk of breast cancer(1). But, in Chinese breast cancer patients low vitamin D status was found to be associated to increased risk  of breast cancer(2).  In breast cancer risk in an Australian population, in differentiation of plasma vitamin D levels indicated that 25(OH)D concentration below 75 nmol/L was  associated with a significantly higher risk of breast cancer(3). In progesterone receptor negative breast cancer, restricted to premenopausal women only, plasma 25(OH)D concentrations. significant inverse association in breast cancer risk(4) In post postmenopausal breast cancer risk, Circulating 25(OH)D3 and 25(OH)D were found to associated with a reduced risk among whites, but not in other ethnic groups(5). In Genetic factor study, some vitamin D receptor (VDR) gene polymorphisms, such as Bsm1, poly(A), Taq1, Apa1 are associated to risk of breast cancer(6). 2,000 IU vitamin D-3 intake inbitbited breast cancer proliferation through reduced COX2 expression(correlated with primary tumor size)(6a). Unfortunately, some suggested that  vitamin D, regardless to dosage do not significantly affected breast cancer risk, treatment efficacy depending to highest dosage of vitamin D and in combination with calcium(6b).

The beneficial
In a few randomized clinical trials (RTC) assessing whether either vitamin D intake or serum levels of 25 hydroxyvitamin D (25OHD) correlate (inversely) with cancer development, suggested that the  vitamin D intake or  serum levels of 25 hydroxyvitamin D (25OHD) reduced risk of cancers by exhibiting its anticancer effects, through the impact in a number of cellular mechanisms(7). In triple negative/basal-like breast cancer, 1,25-dihydroxyvitamin D₃ (1,25D) suppressed multiple proteins that are required for survival of triple-negative/basal-like breast cancer cells through VDR in down regulated breast cancer invasion and metastasis and up regulated anti-profilaerative and apoptic
expression(8). In Two VDRKO (KO240, KO288) and two WT (WT145, WT276) cell lines, 1,25-Dihydroxyvitamin D(3) (1,25D(3)), the active metabolite of vitamin D(3), inhibited the protein expression of VDR trough induced G(0)/G(1) arrest and apoptosis in knockout (VDRKO) and wild type (WT) mice(9). In ER negative, invasive human breast cancer cell line SUM-159PT, 1,25(OH)(2)D(3) (1,25D(3)) and EB1089, a novel vitamin D analogue, reduced SUM-159PT cell growth subsequent to elevation of p27(regulator of cell cycle progression at G₁ and S phase) and p21(cell cycle inhibitor) levels and inhibited SUM-159PT cell invasion through an 8 microM Matrigel (extract in measurement of the invasive activity of tumor cells)(10). In  human breast cancer cell line MCF-7, Calcitriol, calcipotriol (PRI-2201) and tacalcitol (PRI-2191), the synthetic version of vitamin D, showed the antiproliferative activity. AT higher doses of PRI-2202 or PRI-2205, the analog expressed their anti breast cancer activity similar to Tamoxifen through diminished mitochondrial membrane potential( in cell proliferation), as well as the increased phosphatidylserine (cell death) expression with increase in VDR expression in PRI-2201, but not PRI-219,(11). In MCF-7 breast cancer cells, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), a vitamin D analog(1000-fold more active than 1α,25(OH)2D3) suppressed MCF-7 cells growth through cell cycle arrest and apoptotic induction through the upregulation of E-cadherin(tumor suppressors), and the downregulation of Snail, Slug, and Twist, the transcription in  regulate the expression of tumor suppressors such as E-cadherin(12). In BRCA1-deficient(loss of the DNA repair protein 53BP1) breast cancer cells, 1α,25(OH)₂D₃, an active form of vitamin D, stabilized 53BP1 levels in tumor cells and restored the levels of 53BP1, resulting in increased genomic instability in response to PARPi or radiation, and reduced proliferation(13). GcMAF, the vitamin D-binding protein-derived macrophage activating factor exhibited its anti breast cancers effects through stimulation of macrophages(a large white blood cell )in induction of apoptosis and eventually phagocytize them(14). In HER2, accounted for approximately 20% of human breast cancer cases,  Gemini vitamin D analog BXL0124, decreased activation of ErbB2 as well as other ErbB receptors, ErbB1 and ErbB3, through repression of activated-Erk1/2(cell regulation), activated-Akt(multiple cellular processes, including apoptosis), c-Myc(a regulator gene), CycD1(regulating cell cycle progression), and Bcl2(family of regulator proteins that regulate cell death)(15). In  ER+ BCa., vitamin D suppressed the ER expression and estrogen-mediated signaling in BCa cells(16). In MCF-7 and MCF-7/VD(R) breast cancer cells, insulin-like growth factor I (IGF-I) in 1, 25-dihydroxyvitamin D3 (1, 25-D3)inhibited IGF-I/Akt pathways to cause apoptosis(17). In MCF10DCIS cells, Gemini vitamin D BXL0124 is found to decrease CD44 protein level(a transmembrane glycoprotein, is a major receptor for extracellular proteins involved in invasion and metastasis of human cancers), suppressed STAT3 (development, progression, and maintenance of many human tumors)signaling, and inhibited invasion and proliferation(18) and inhibited the growth of ErbB2 overexpressing mammary tumors through regulating the ErbB2/AKT/ERK(proliferation) signaling pathways in ErbB2-positive mammary tumor growth(18). In MCF-7 breast cancer cells, L-buthionine-S,R-sulfoximine, a glutathione-depleting drug enhanced inhibition of 1,25(OH)(2)D(3) in all transformed breast cell lines through ROS mediation induced apoptosis(19).

The disagreement of amount of vitamin D intake and plasma level may still need further study, but the effective of vitamin D in reduced risk and treating breast caner may not be denied. Over doses of vitamin D supplement may cause excessive calcium absorption, calcification, Urinary stones etc. please make sure to follow the guideline of the Institute of Medicine of the National Academies.
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References
(1) Plasma vitamin D levels, menopause, and risk of breast cancer: dose-response meta-analysis of prospective studies by Bauer SR, Hankinson SE, Bertone-Johnson ER, Ding EL.(Pubnmed)
(2) Correlates of 25-Hydroxyvitamin D among Chinese Breast Cancer Patients by Shi L¹, Nechuta S², Gao YT³, Zheng Y⁴, Dorjgochoo T², Wu J², Cai Q², Zheng W², Lu W⁴, Shu XO².(PubMed)
(3) Association between 25-hydroxyvitamin D concentration and breast cancer risk in an Australian population: an observational case-control study by Bilinski K, Boyages J.(PubMed)
(4) Plasma 25-hydroxyvitamin D and premenopausal breast cancer risk in a German case-control study by Abbas S, Chang-Claude J, Linseisen J.(PubMed)
(5) Plasma 25-hydroxyvitamin D3 is associated with decreased risk of postmenopausal breast cancer in whites: a nested case-control study in the multiethnic cohort study by Kim Y, Franke AA, Shvetsov YB, Wilkens LR, Cooney RV, Lurie G, Maskarinec G, Hernandez BY, Le Marchand L, Henderson BE, Kolonel LN, Goodman MT.(PubMed)
(6) Vitamin D receptor gene polymorphisms in breast and renal cancer: Current state and future approaches (Review) by Khan MI¹, Bielecka ZF¹, Najm MZ², Bartnik E³, Czarnecki JS⁴, Czarnecka AM¹, Szczylik C (PubMed)
(6a) Vitamin D favorably alters the cancer promoting prostaglandin cascade by Qin W, Smith C, Jensen M, Holick MF, Sauter ER.(PubMed)
(6b) Vitamin d supplementation and breast cancer prevention: a systematic review and meta-analysis of randomized clinical trials by Sperati F, Vici P, Maugeri-Saccà M, Stranges S, Santesso N, Mariani L, Giordano A, Sergi D, Pizzuti L, Di Lauro L, Montella M, Crispo A, Mottolese M, Barba M.(PubMed)
(7) Vitamin D and cancer: the promise not yet fulfilled by Bikle DD(PubMed).
(8) Modeling vitamin D actions in triple negative/basal-like breast cancer by Laporta E, Welsh J.(PubMed)
(9) Characterization of mammary tumor cell lines from wild type and vitamin D3 receptor knockout mice by Zinser GM, McEleney K, Welsh J.(PubMed)
(10) Efficacy of Vitamin D compounds to modulate estrogen receptor negative breast cancer growth and invasion by Flanagan L, Packman K, Juba B, O'Neill S, Tenniswood M, Welsh J.(PubMed).
(11) Synthesis and Biological Activity of Diastereomeric and Geometric Analogs of Calcipotriol, PRI-2202 and PRI-2205, Against Human HL-60 Leukemia and MCF-7 Breast Cancer Cells. by Milczarek M, Chodyński M, Filip-Psurska B, Martowicz A, Krupa M, Krajewski K, Kutner A, Wietrzyk J.(PubMed)
(12) MART-10, a less calcemic vitamin D analog, is more potent than 1α,25-dihydroxyvitamin D3 in inhibiting the metastatic potential of MCF-7 breast cancer cells in vitro by Chiang KC, Chen SC, Yeh CN, Pang JH, Shen SC, Hsu JT, Liu YY, Chen LW, Kuo SF, Takano M, Kittaka A, Sun CC, Juang HH, Chen TC.(PubMed)
(13) Novel roles of 1α,25(OH)2D3 on DNA repair provide new strategies for breast cancer treatment by Gonzalo S.(PubMed).
(14) A novel role for a major component of the vitamin D axis: vitamin D binding protein-derived macrophage activating factor induces human breast cancer cell apoptosis through stimulation of macrophages by Thyer L, Ward E, Smith R, Fiore MG, Magherini S, Branca JJ, Morucci G, Gulisano M, Ruggiero M, Pacini S.(PubMed)
(15) Oral administration of a gemini vitamin D analog, a synthetic triterpenoid and the combination prevents mammary tumorigenesis driven by ErbB2 overexpression by So JY, Wahler JE, Yoon T, Smolarek AK, Lin Y, Shih WJ, Maehr H, Uskokovic M, Liby KT, Sporn MB, Suh N.(PubMed).
(16) Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements by Swami S, Krishnan AV, Peng L, Lundqvist J, Feldman D.(PubMed).
(17) Role of insulin-like growth factor binding protein-3 in 1, 25-dihydroxyvitamin-d 3 -induced breast cancer cell apoptosis by Brosseau C, Pirianov G, Colston KW.(PubMed)
(18) Targeting CD44-STAT3 signaling by Gemini vitamin D analog leads to inhibition of invasion in basal-like breast cancer by So JY, Smolarek AK, Salerno DM, Maehr H, Uskokovic M, Liu F, Suh N.(PubMed)
(19) Buthionine sulfoximine and 1,25-dihydroxyvitamin D induce apoptosis in breast cancer cells via induction of reactive oxygen species by Bohl LP, Liaudat AC, Picotto G, Marchionatti AM, Narvaez CJ, Welsh J, Rodriguez VA, Tolosa de Talamoni NG.(PubMed)

Breast cancer in Vitamin C.s Point of View

By Kyle J. Norton (Draft Article)

Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin, found in fresh fruits, berries and green vegetables. It is best known for its free radical scavengers activity and in regenerating oxidized vitamin E for immune support. Epidemiological studies linking vitamin C in reduced risk of breast cancer may be inconclusive(1)(1a)(1b), but no doubt in acceptance of improved quality of life(2).
 Macro nutrients intake may form an important parts in breast cancer patients in providing vital support for treatment.(3). There was a report of intake of supplementation of multiple vitamin, beta-carotene, vitamin C, vitamin E and zinc in postmenopausal women for 10 or more years may protect women from developing breast cancer(3a). 
Women with breast cancer in the Indian population, were found to have a lower levels of mean vitamin C, vitamin E and selenium than controls. if the levels of mean vitamin C, vitamin E and selenium increased by 1 unit, the risk of breast cancer was reduced by 7%(3b).
In breast cancer survival, dietary vitamin C intake before breast cancer diagnosis may be associated with breast cancer survival. but not in post-diagnosis(4). High intake of ascorbic acid was in associated to reduce risk of breast cancer incidence in overweight women and women with high consumption of linoleic acid (average consumption of more than 6 grams of linoleic acid per day)(5) and insignificant risk in other breast cancer patients(6). On inflammation in cancer patients, high dose intravenous ascorbic acid therapy, decreased the levels of C-reactive protein thus reduced inflammation correlated with decreases in tumor marker levels(7). Vitamin C supplements and Anthocyanin (Ixor®) at a dose of 2 tablets/day, starting from 10 days before the radiation treatment until 10 days after the end of treatment was found to be protective against skin damage to patient undergoing adjuvant chemotherapy(8).
In estrogen-induced breast carcinogenesis, vitamin C (Vit C) and butylated hydroxyanisole (BHA) found to be effective in inhibition of 17β-estradiol (E2)-mediated oxidative stress and oxidative DNA damage by preventing the decreasing NRF2(antioxidant response pathway) and OGG1(base excision repair.) levels(9). In the study of the same but in MCF-10A cells, the combination also decreased E2-mediated increase in 8-OHdG(Marker detected in cancer patients) levels in the mammary tissues, induced SOD3 (Extracellular superoxide dismutase [Cu-Zn]) through NRF2 Pathway to defense against oxidative stress and in the prevention of estrogen-mediated breast cancer(10).
 An increased expression of the miR-93(Regulate Expression of Tumor Suppressor Gene) was found in 17β-estradiol (E2)-treated mammary tissues and in human breast cell lines, treatment with vitamin C reverted E2-mediated increase in miR-93 levels by upregulating expression NRF2 antioxidant response pathway(11). In 4T1 breast cancer cells in vitamin C-deficient mice, Ascorbic acid delay the progress of metastasis, tumor growth and inflammatory cytokine secretion (decreased serum inflammatory cytokine interleukin (IL)-6) as well as enhanced encapsulation of tumors(12). In L-ascorbate (L-ascorbic acid, vitamin C), increasing the concentration exhibited the autophagic damage to functional SVCT-2(antibody) sensitizes breast cancer cells(13). In B16F10, L-ascorbate also caused induction of a prooxidant state,  subsequent reduction in mitochondrial membrane potential to induced apoptosis in a caspase-8(Cell apoptosis)-independent manner(14). In  the usage of glucan, resveratrol and vitamin C,  the combination showed the strongest activator of phagocytosis (immune cell activation) and antibody formation to suppress the growth of breast and lung tumors, through stimulation of apoptosis(15). In  4T1 cancer cell line, combined with ascorbate, Mn(III)N-alkylpyridylporphyrins (MnPs) inhibited cancer cells via peroxide produced outside of the cell through enhancing tumour oxidative stress and tumor growth suppression(16). In Ataxia telangiectasia mutated (ATM)  diplotype on the breast cancer, vitamin C enhanced the increase of ATM to reduce the risk of breast cancer.(17). In E(2) metabolism and oxidant stress in involved in estrogen-induced breast cancer development, vitamin C reducesd the incidence of estrogen-induced mammary tumors, increased tumor latency and decreases oxidative stress in vivo(18). In SK-BR3 and Hs578T breast cancer cell lines, Vitamin C treatment induced AIF(apoptosis-inducing factor) mediation of cell death pathway of the breast cancer cell lines independent to caspase pathway(19).
In human breast cancer cell line MCF-7, combination of Retinoic acid and ascorbic acid inhibited the proliferation of human breast cancer cells through altering their gene expression related to antioxidation processes and the proliferation inhibitory pathway(20).

Taking all together, without going into reviews, vitamin C is found to be effective in reduced risk and a potent agent for treatment of breast cancer. Daily ingestion of high-dose vitamin C may be considered safe, but in rare incidence, overdoses in a prolonged period of time, may cause intra-renal oxalate crystal deposition, a fatal nephrotoxicity(21)(22).
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References
(1) Vitamin C suppresses cell death in MCF-7 human breast cancer cells induced by tamoxifen by Subramani T, Yeap SK, Ho WY, Ho CL, Omar AR, Aziz SA, Rahman NM, Alitheen NB.(PubMed)
(1a) Vitamin supplement consumption and breast cancer risk: a review by Misotti AM, Gnagnarella P.(PubMed)
(1b) Dietary fiber, vitamins A, C, and E, and risk of breast cancer: a cohort study by Rohan TE, Howe GR, Friedenreich CM, Jain M, Miller AB.(PubMed)
(2) Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany by Vollbracht C, Schneider B, Leendert V, Weiss G, Auerbach L, Beuth J.(PubMed)
(3) Nutritional assessment of selected patients with cancer.

Surwillo A, Wawrzyniak A.(PubMed)
(3a) Antioxidants and breast cancer risk- a population-based case-control study in Canada by Pan SY, Zhou J, Gibbons L, Morrison H, Wen SW; Canadian Cancer Registries Epidemiology Research Group [CCRERG].(PubMed)
(3b) Association between breast cancer and vitamin C, vitamin E and selenium levels: results of a case-control study in India by Singh P, Kapil U, Shukla NK, Deo S, Dwivedi SN.(PubMed)

(4) Vitamin C intake and breast cancer mortality in a cohort of Swedish women by Harris HR, Bergkvist L, Wolk A.(PubMed)

(5) Dietary antioxidant vitamins, retinol, and breast cancer incidence in a cohort of Swedish women by Michels KB, Holmberg L, Bergkvist L, Ljung H, Bruce A, Wolk A.(PubMed)

(6) Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study. by Verhoeven DT, Assen N, Goldbohm RA, Dorant E, van 't Veer P, Sturmans F, Hermus RJ, van den Brandt PA.(PubMed).

(7) Effect of high-dose intravenous vitamin C on inflammation in cancer patients by Mikirova N, Casciari J, Rogers A, Taylor P.(PubMed)
(8) Skin toxicity from external beam radiation therapy in breast cancer patients: protective effects of Resveratrol, Lycopene, Vitamin C and anthocianin (Ixor®) by Di Franco R, Calvanese M, Murino P, Manzo R, Guida C, Di Gennaro D, Anania C, Ravo V.(PubMed)

(9) Antioxidant-mediated up-regulation of OGG1 via NRF2 induction is associated with inhibition of oxidative DNA damage in estrogen-induced breast cancer by Singh B, Chatterjee A, Ronghe AM, Bhat NK, Bhat HK(PubMed).

(10) Superoxide dismutase 3 is induced by antioxidants, inhibits oxidative DNA damage and is associated with inhibition of estrogen-induced breast cancer by Singh B, Bhat HK.(PubMed)

(11) MicroRNA-93 regulates NRF2 expression and is associated with breast carcinogenesis by Singh B, Ronghe AM, Chatterjee A, Bhat NK, Bhat HK.(PubMed)

(12) Ascorbate supplementation inhibits growth and metastasis of B16FO melanoma and 4T1 breast cancer cells in vitamin C-deficient mice by Cha J, Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M.(PubMed)

(13) SVCT-2 in breast cancer acts as an indicator for L-ascorbate treatment by Hong SW, Lee SH, Moon JH, Hwang JJ, Kim DE, Ko E, Kim HS, Cho IJ, Kang JS, Kim DJ, Kim JE, Shin JS, Jung DJ, Jeong YJ, Cho BJ, Kim TW, Lee JS, Kang JS, Hwang YI, Noh DY, Jin DH, Lee WJ.(PubMed)

(14) L-ascorbic acid (vitamin C) induces the apoptosis of B16 murine melanoma cells via a caspase-8-independent pathway by Kang JS, Cho D, Kim YI, Hahm E, Yang Y, Kim D, Hur D, Park H, Bang S, Hwang YI, Lee WJ.(PubMed)
(15) Combination of glucan, resveratrol and vitamin C demonstrates strong anti-tumor potential.

Vetvicka V, Vetvickova J.(PubMed)

(16) Cytotoxic effects of Mn(III) N-alkylpyridylporphyrins in the presence of cellular reductant, ascorbate by Ye X, Fels D, Tovmasyan A, Aird KM, Dedeugd C, Allensworth JL, Kos I, Park W, Spasojevic I, Devi GR, Dewhirst MW, Leong KW, Batinic-Haberle I.(PubMed)

(17) Antioxidant vitamins intake, ataxia telangiectasia mutated (ATM) genetic polymorphisms, and breast cancer risk by Lee SA, Lee KM, Lee SJ, Yoo KY, Park SK, Noh DY, Ahn SH, Kang D.(PubMed)

(18) Vitamin C and alpha-naphthoflavone prevent estrogen-induced mammary tumors and decrease oxidative stress in female ACI rats by Mense SM, Singh B, Remotti F, Liu X, Bhat HK.(PubMed)

(19) Ascorbate (vitamin C) induces cell death through the apoptosis-inducing factor in human breast cancer cells by Hong SW, Jin DH, Hahm ES, Yim SH, Lim JS, Kim KI, Yang Y, Lee SS, Kang JS, Lee WJ, Lee WK, Lee MS.(PubMed)

(20) Retinoic acid and ascorbic acid act synergistically in inhibiting human breast cancer cell proliferation by Kim KN, Pie JE, Park JH, Park YH, Kim HW, Kim MK.(PubMed)

(21) Fatal vitamin C-associated acute renal failure by McHugh GJ, Graber ML, Freebairn RC.(PubMed)

(22) Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis by Urivetzky M, Kessaris D, Smith AD.(PubMed)

Breast cancer in Vitamin A's Points of View

 By Kyle J. Norton (Draft article)

Vitamins form an important part in human diet. Epidemiological studies, linking vitamin A in reduced risk of breast cancer have produced uncleared result(1)(1a)(1b). But certain studies, showed vitamin A in form of retinoids and carotenoids is effective in inhibition of breast cancer cell lines through many anti porfilerative and apoptotic pathways.

Vitamin A is a general term of Vitamin A Retinol, retinal, beta-carotene, alpha-carotene, gamma-carotene, and beta-cryptoxanthin best known for its functions for vision health and antioxidant scavenger and essential for growth and differentiation of a number of cells and tissues.
Recommended intakes of vitamin A, according to  the Institute of Medicine of the National Academies (formerly National Academy of Sciences) is 600 µg daily as extremely high doses (>9000 mg) can be toxicity as causes of dry, scaly skin, fatigue, nausea, loss of appetite, bone and joint pains, headaches, etc.

1. Retinols
Lack of the retinoic acid receptor beta (RAR beta) gene expression causes of abnormal regulation by retinoic acid (RA) are common features in human lung cancer and breast cancer cells(2)
Suggestion of using retinoids, the natural and synthetic vitamin A derivatives in chemoprevention because of its function in modification of abnormal dell growth in Cancer tissues(3) by exerting anticancer effects through its retinoid receptors, the RA receptors (RARs) and retinoid X receptors (RXRs)in regualating the target gene causes of the diseases(4). In SK-BR-3 and T47D human breast cancer cells, retinoid showed to be effectively in regulates mammary epithelial cell growth and differentiation through signaling via retinoic acid (RA) and retinoid X receptors (RARs and RXRs) leading to apoptosis in ER- SK-BR-3 and ER+ T47D breast cancer cells(5). All-trans retinoic acid(ATRA), a synthetic version of vitamin A, showed effectively in inhibition of  breast cancer stem cells, NCSCs and CSCs, through impairment of the self-renewing ability of CSCs and promotion of  CSCs to differentiate(6). In human breast cancer cell lines of MDA-MB-468 and MCF-7, ATRA inhibited the proliferation and the expression of BP1(expression of BP1 protein correlated with breast tumor progression and invasion) in breast cancer cells(7).
 In human breast cancer MDA-MB-231 cells, the synthetic retinoid 4-amino-2-tri-fluoromethyl-phenyl ester (ATPR) inhibited cells reduced migration and reduced phosphorylation of ERK(cellular proliferation, differentiation, and survival), JNK(cellular apoptosis) and p38(highly expressed in aggressive and invasive breast cancers) in breast cancer(8). Retinoic acid (RA), a vitamin A metabolite, induced breast cancer cell apoptosis through type I IFN autocrine (activation of T cells, B cells, and natural killer cells)signaling, caspase-8 and caspase-3(Cell apoptosis) activation, as well as TRAIL(induces the process of cell death) signaling(9). Taking to these accounts, Retinols may be beneficial as a potent agent in preventing and treating breast cancer.

2. Carotenoids(beta-carotene, alpha-carotene, gamma-carotene and beta-cryptoxanthin)
Carotenoids, plant pigments, converted to vitamin A after intake, though to play an important role in prevention and treatment of some diseases through it antioxidant effects.
In postmenopausal women, dietary beta-carotene intake is found to be effective in reduced risk of breast caner with or without high alcohol intake(11)(12)(13)(16). Other studies of circulating carotenoids, also showed that high levels of beta carotene circulation are associated to decreased risk of breast cancer(14).
In the risk of breast cancer by estrogen receptor (ER) and progesterone receptor (PR),  β-carotene intakes were inversely associated with the risk of ER-negative (ER-)but not ER- positive breast cancer cell lines(15). In genetic polymorphisms of NOS3, intake of β-carotene modified and protected against risk of breast cancer predominantly in individuals with the TG:TG diplotype of NOS3(17). In related with other supplements, intake of multivitamins including  beta-carotene, vitamin C, vitamin E and zinc for 10 Years or more may protect from developing breast cancer in postmenopausal women(18). biologically, the protection of antioxidants including β-carotene against breast cancer was associated to activation of  immune response in the course of the disease(19). In smokers, dietary alpha-carotene and beta-carotene are associated with reduced risk of breast cancer among women who do not use dietary supplements(20).
In estrogen receptor (ER) and progesterone receptor (PR) status, intakes of α-carotene was associated with reduced risk of ER-, but not ER+, breast cancer(15). In women with high mammographic density, using a computer-assisted thresholding method, total carotenoids were associated with a 50% reduction in breast cancer risk(21). In a total of 969 cases of breast cancer diagnosed after blood draw and prior to June 1, 1998, alpha carotene was inversely associated in reduced risk of breast cancer greater for invasive cancers with nodal metastasis(22). In invasive breast cancer, high consumption of carotenoids may reduce risk of of breast cancer in premenopausal but not postmenopausal women, particularly among smokers, including alpha-carotene(23). In comparison of blood concentrations of carotenoids and carotenoids assessed by dietary questionnaires, showed strong relationship between biomarkers and the reduced risk of breast cancer(24). In breast cancers defined by estrogen receptor (ER) and progesterone receptor (PR) status, dietary alpha-carotene was inversely associated with risk of ER+PR+breast cancer, but not with other breast cancer groups jointly defined by ER and PR status(25). In the study of gene O(6)-methylguanine DNA methyl-transferase (MGMT) involved in cellular defense against, dietary antioxidants are associated to inversely reduce risk of breast cancer through possible modulation of polymorphisms in MGMT(26).
In malignant melanoma, mammary carcinoma and lung adenocarcinoma cells growth, water and ethanol extracts from glaucophyte Cyanophora paradoxa (Cp) with Pheophorbide a, β-cryptoxanthin and zeaxanthin were found to significantly inhibit the growth of the three cancer cell lines mentioned above in vitro, at 100 µg · mL..(27). In the study of various phytochemicals and cancer risk.In the study the associations of plasma levels of tocopherols, retinol, carotenoids with the risk of developing breast cancer among Chinese women, high levels of plasma lycopene other than trans, 5- and 7-cis or trans alpha-cryptoxanthin were inversely associated with the risk of developing breast cancer(28).

Dietary vitamin A, includes retinol, retinal, retinoic acid, and several provitamin A carotenoids has been found significantly in reduced risk and treatment of  breast cancer through modification of malignant cell growth, expression of down-regulation of pro proliferative and up-regualtion of apoptotic pathway. Regardless to it anti-breast cancer effects, overdoses can led to toxic symptoms. Please make sure you follow the guideline of the Institute of Medicine of the National Academies.
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References
(1) Vitamin supplement consumption and breast cancer risk: a review by Misotti AM, Gnagnarella P.(PubMed)
(1a) Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study by Verhoeven DT, Assen N, Goldbohm RA, Dorant E, van 't Veer P, Sturmans F, Hermus RJ, van den Brandt PA.(PubMed)
(1b)Micronutrient intake and breast cancer characteristics among postmenopausal women by Roswall N, Olsen A, Christensen J, Dragsted LO, Overvad K, Tjønneland A.(PubMed)


(2) Retinoid receptors in human lung cancer and breast cancer by Zhang XK, Liu Y, Lee MO.(PubMed)
(3) Retinoids in cancer chemoprevention by Okuno M, Kojima S, Matsushima-Nishiwaki R, Tsurumi H, Muto Y, Friedman SL, Moriwaki H.(PubMed)
(4) Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids by Wu Q, Dawson MI, Zheng Y, Hobbs PD, Agadir A, Jong L, Li Y, Liu R, Lin B, Zhang XK.(PubMed)
(5) Activation of retinoic acid receptor alpha is sufficient for full induction of retinoid responses in SK-BR-3 and T47D human breast cancer cells by Schneider SM, Offterdinger M, Huber H, Grunt TW.(PubMed)
(6) [All-trans retinoic acid effectively inhibits breast cancer stem cells growth in vitro].

[Article in Chinese] by Zeng WG, Hu P, Wang JN, Liu RB.(PubMed)

(7) [Effects of all trans retinoic acid on the expression alterations of beta-protein 1 in human breast cancer cell lines of MDA-MB-468 and MCF-7].[Article in Chinese by Su J, Li MQ, Zhong GS.(PubMed)

(8) A novel all-trans retinoid acid derivatives inhibits the migration of breast cancer cell lines MDA-MB-231 via myosin light chain kinase involving p38-MAPK pathway by Wang B, Yan Y, Zhou J, Zhou Q, Gui S, Wang Y.(PubMed)

(9) Synergy between RA and TLR3 promotes type I IFN-dependent apoptosis through upregulation of TRAIL pathway in breast cancer cells by Bernardo AR, Cosgaya JM, Aranda A, Jiménez-Lara AM.(PubMed)
(10) Cis-retinol dehydrogenase: 9-cis-retinol metabolism and its effect on proliferation of human MCF7 breast cancer cells by Paik J, Blaner WS, Swisshelm K.(PubMed)
(11) Dietary beta-carotene, vitamin C and E intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) by Nagel G, Linseisen J, van Gils CH, Peeters PH, Boutron-Ruault MC, Clavel-Chapelon F, Romieu I, Tjønneland A, Olsen A, Roswall N, Witt PM, Overvad K, Rohrmann S, Kaaks R, Drogan D, Boeing H, Trichopoulou A, Stratigakou V, Zylis D, Engeset D, Lund E, Skeie G, Berrino F, Grioni S, Mattiello A, Masala G, Tumino R, Zanetti R, Ros MM, Bueno-de-Mesquita HB, Ardanaz E, Sánchez MJ, Huerta JM, Amiano P, Rodríguez L, Manjer J, Wirfält E, Lenner P, Hallmans G, Spencer EA, Key TJ, Bingham S, Khaw KT, Rinaldi S, Slimani N, Boffetta P, Gallo V, Norat T, Riboli E.(PubMed)
(12) Beta-carotene intake and risk of postmenopausal breast cancer by Jumaan AO, Holmberg L, Zack M, Mokdad AH, Ohlander EM, Wolk A, Byers T.(PubMed)
(13) Dietary carotenoids and risk of breast cancer in Chinese women by Huang JP, Zhang M, Holman CD, Xie X.(PubMed)
(14) Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies by Eliassen AH, Hendrickson SJ, Brinton LA, Buring JE, Campos H, Dai Q, Dorgan JF, Franke AA, Gao YT, Goodman MT, Hallmans G, Helzlsouer KJ, Hoffman-Bolton J, Hultén K, Sesso HD, Sowell AL, Tamimi RM, Toniolo P, Wilkens LR, Winkvist A, Zeleniuch-Jacquotte A(PubMed)
(15). Carotenoid intakes and risk of breast cancer defined by estrogen receptor and progesterone receptor status: a pooled analysis of 18 prospective cohort studies by Zhang X, Spiegelman D, Baglietto L, Bernstein L, Boggs DA, van den Brandt PA, Buring JE, Gapstur SM, Giles GG, Giovannucci E, Goodman G, Hankinson SE, Helzlsouer KJ, Horn-Ross PL, Inoue M, Jung S, Khudyakov P, Larsson SC, Lof M, McCullough ML, Miller AB, Neuhouser ML, Palmer JR, Park Y, Robien K, Rohan TE, Ross JA, Schouten LJ, Shikany JM, Tsugane S, Visvanathan K, Weiderpass E, Wolk A, Willett WC, Zhang SM, Ziegler RG, Smith-Warner SA.(PubMed)
(16) Carotenoids and breast cancer risk: a meta-analysis and meta-regression by Hu F, Wang Yi B, Zhang W, Liang J, Lin C, Li D, Wang F, Pang D, Zhao Y.(PubMed)
(17) Combined effects of antioxidant vitamin and NOS3 genetic polymorphisms on breast cancer risk in women by Lee SA, Lee KM, Yoo KY, Noh DY, Ahn SH, Kang D.(PubMed)
(18) Antioxidants and breast cancer risk- a population-based case-control study in Canada by Pan SY, Zhou J, Gibbons L, Morrison H, Wen SW; Canadian Cancer Registries Epidemiology Research Group [CCRERG].(PubMed).
(19) Antioxidant vitamins and cytokines are altered in breast cancer by Abranches MV, Mendes MC, Pena Gd, Maia YC, Ribeiro SM, Franceschini Sdo C, de Paula SO, de Freitas RN, Peluzio MC.(PubMed)
(20) Dietary carotenoids and risk of hormone receptor-defined breast cancer in a prospective cohort of Swedish women by Larsson SC, Bergkvist L, Wolk A.(PubMed)
(21) Circulating carotenoids, mammographic density, and subsequent risk of breast cancer by Tamimi RM, Colditz GA, Hankinson SE.(PubMed)
(22) Plasma carotenoids, retinol, and tocopherols and risk of breast cancer by Tamimi RM, Hankinson SE, Campos H, Spiegelman D, Zhang S, Colditz GA, Willett WC, Hunter DJ.(PubMed)
(23) Dietary carotenoids and the risk of invasive breast cancer by Mignone LI, Giovannucci E, Newcomb PA, Titus-Ernstoff L, Trentham-Dietz A, Hampton JM, Willett WC, Egan KM.(PubMed)
(24) Dietary compared with blood concentrations of carotenoids and breast cancer risk: a systematic review and meta-analysis of prospective studies by Aune D, Chan DS, Vieira AR, Navarro Rosenblatt DA, Vieira R, Greenwood DC, Norat T.(PubMed)
(25) Selected antioxidants and risk of hormone receptor-defined invasive breast cancers among postmenopausal women in the Women's Health Initiative Observational Study by Cui Y, Shikany JM, Liu S, Shagufta Y, Rohan TE.(PubMed)
(26) MGMT genotype modulates the associations between cigarette smoking, dietary antioxidants and breast cancer risk by Shen J, Terry MB, Gammon MD, Gaudet MM, Teitelbaum SL, Eng SM, Sagiv SK, Neugut AI, Santella RM.(PubMed)
(27) Antiproliferative activity of Cyanophora paradoxa pigments in melanoma, breast and lung cancer cells by Baudelet PH, Gagez AL, Bérard JB, Juin C, Bridiau N, Kaas R, Thiéry V, Cadoret JP, Picot L.(PubMed)
(28) Plasma carotenoids, tocopherols, retinol and breast cancer risk: results from the Shanghai Women Health Study (SWHS) by Dorjgochoo T, Gao YT, Chow WH, Shu XO, Li H, Yang G, Cai Q, Rothman N, Cai H, Franke AA, Zheng W, Dai Q.(PubMed)

Prostate Cancer in Herbs' Points of View

 By Kyle J. Norton (Draft article)

The widespread of prostate cancer, once considered as a disease of aging male, now have become major concerns of governments and scientific community in South East Asian with tendency to spread to younger age population. Suggestions emerged of over consuming bad fats in any time in history accompanied with unhealthy diet and life style may be the possible causes of the disease, linking to the economic prosperity over 2 decades. Herbal medicine for diseases' management have been prescribed in folk medicine over thousands of year as one of best medicine of nature in preventing and treating diseases, including prostate cancer.
Prostate cancer is defined as a condition in which the cells of prostate has become cancerous, causing abnormal cell growth with possibility of spreading to the distant parts of the body. Most prostate cancers are slow growing and enlarged prostate and prostate cancer may be detected during physical (rectum) exams.
1. Aloe vera
Aloe Vera is species of succulent plant in the genus Aloe, belonging to the Family Xanthorrhoeaceae, native to Sudan. It has become very popular for commercial cultivation due to its health benefits. Aloe vera has been used in herbal medicine in treating many kinds of disease, including wound, burn healing, minor skin infections, sebaceous cysts, diabetes, and elevated of cholesterol, etc. It is also one of many popular herb studied in scientific ways with some conflicted results.
Aloe-emodin, a chemical constituent in Aloe vera, inhibited both proliferation and anchorage-independent growth of PC3 cells through activation of the downstream substrates of mTORC2, Akt and PKCα causes of apoptosis, cell proliferation(1). prostate cancer, LNCaP expression of N-acetylated by cytosolic N-acetyltransferase (NAT) activity and mRNA inhibited by aloe-emodin in doses depending mannerthrough its kinase activity in cellular transformation(2)(3).

2. Cascara sagrada
Cascara sagrada is a species of buckthorn, genus Rhamnus, belonging to the family Rhamnaceae, native to western North America, it's bark has been used in traditional medicine for gastrointestinal support. and it is thought to have a laxative and natural cleansing, etc., effect.
Emodin, a cemical compoubd found in Cascara sagrada, inhibited cellular migration and invasion in prostate cancer through downregulate CXCR4 expression which is involved in promoting invasion and metastasis in tumors(4). In human prostate cancer cell LNCaP, amodin increased apoptosis and  decreased in cell proliferation through down regualting the expression of expression of androgen receptor (AR) and prostate specific antigen (PSA) and upregulating the expression of p53(Anti tumor antigen) and p21(( regulator of cell cycle progression at G₁ and S phase)(5), In other study, Emodin enhanced the  cytotoxic effectiveness of chemotherapeutic drugs in prostate cancer cells through ROS(reactive oxygen spiecies)-mediated suppression of multidrug resistance and hypoxia inducible factor-1(influence cell metabolism, cell survival and angiogenesis to maintain biological homeostasis)(6).

3. Green tea
Green tea contains more amount of antioxidants than any drinks or food with the same volume, and is the leaves of Camellia sinensis, undergone minimal oxidation during processing, originated from China. Green tea has been a precious drink in traditional Chinese culture and used exceptional in socialization for more than 4000 thousand years. Because of their health benefits, they have been cultivated for commercial purposes all over the world.
Epigallocatechin-3-gallate (Chit-nanoEGCG), a phytochemical in green tea, exerted a significant inhibition of tumor growth and secreted prostate-specific antigen levels compared with EGCG and control groups, trough induction of poly (ADP-ribose) polymerases cleavage, increase in the protein expression of Bax(involved in p53-mediated apoptosis)  with accompanied decrease in Bcl-2(family of regulator proteins that regulate cell death), and activation of caspases(mechanisms of apoptosis) and reduction in Ki-67 and proliferating cell nuclear antigen(7). In androgen-independent prostate cancer, synthetic derivative, EGCG (EGCG-P) and EGCG treatment suppressed the growth of the tumor correlated with the decrease of serum PSA level together with the reduction in tumor angiogenesis and an increase in apoptosis on prostate cancer cells(8). In anticancer drug cisplatin, EGCG ehnaced the effectiveness of the chemo agent in reduction of cell survival of prostate cancer cell line PC3 and induced apoptosis(9).

4. Pomegranate
Pomegranates is a fruit-bearing small tree, genus Punica, belonging to family Lythraceae, native to Iran but has been cultivated in Asian since ancient time.
POMx, a pomegranate extract (PE) fomula, exhibited potent in vitro cytotoxicity in metastatic castration-resistant PCa cells through inhibition of survivin, induced apoptosis, retarded C4-2 tumor growth in skeleton and significantly enhanced the efficacy of docetaxel(Chemodrug) in athymic nude mice(10). Ellagic acid (EA) converted from Ellagitannins (ETs) found in from pomegranate juice (PJ) showed to induce apoptosis in both cell lines, DU-145 and PC-3 through induced  cell cycle arrest in S phase associated with decreased cyclin B1 and cyclin D1 levels in regulation ofcell cycle progression(11). Pomegranate juice (PJ) PJ components luteolin, ellagic acid, and punicic acid together found to inhibit growth of hormone-dependent and hormone-refractory prostate cancer cells and their migration, increase the expression of cell adhesion genes and decrease expression of genes involved in cell cycle control through suppression microRNAs (miRNAs), decrease several oncogenic miRNAs, and inhibit the chemokines receptor type 4 (CXCR4)/SDF1α chemotaxis axis(decreased PSA cell migration)(12).

6. Garlic
Garlic (Allium sativum) is a species in the onion genus, belonging to family Amaryllidaceae, native to central Asia. It has been used popularly in traditional and Chinese medicine in treating common cold and flu to the Plague, blood pressure cholesterol levels, natural antibiotic, etc.
In androgen-independent prostate cancer, garlic-derived organosulfur compound S-allylmercaptocysteinesuppresses invasion and cell motility of androgen-independent prostate cancer cells via the up-regulation of cell-adhesion molecule E-cadherin(Loss of E-cadherin expression has been implicated in cancer progression and metastasis)(16). Garlic compound diallyl disulfid,a oil soluble organosulfur compound of garlic, exerted its antiproliferative and inhibited effect on prostate cancer cells, through induction of DNA damage in a dose dependent manner(17). Garlic constituent diallyl trisulfide (DATS), induced apoptosis in prostate cancer cells is mediated in part by suppression of XIAP(a protein that stops apoptotic cell death) protein expression(18).

7. Chamomile
Chamomile is also known as camomile, common name of many species daisy-like plants in the family Asteraceae. The herb has been used in traditional medicine as antispasmodic and anti-inflammatory constituents and to treat menstrual cramps and sleep disorders, reduce cramping and spastic pain in the bowels, relieve excessive gas and bloating in the intestine, etc.
Phenolic profile of chamomile showed to inhibited the cell proliferation and to reduce IL-8 (an important mediator of the immune reaction in the innate immune system response) levels in PC3 prostate cancer cells(19). Traditional Botanical Supplement-101 (TBS-101), including the extracts of Panax ginseng, cranberry, green tea, grape skin, grape seed, Ganoderma lucidum and chamomile, showed to inhibit in hormone-refractory PC-3 cells and large aggressive PC-3 tumors cell growth in a dose-dependent manner(20). In human cancer cell lines PC-3, A-549 and MCF-7, Chamomile's essential oils, induced cytotoxicity of prostate carcinoma cell (PC-3), significantly stronger than on human lung carcinoma (A549) and human breast cancer (MCF-7) cell lines(21).

8. Onion
The onion is a close relation of garlic plant in the genus Allium, belonging to the family Alliaceae.  It is often called the "king of vegetables" because of its pungent taste and found in a large number of recipes and preparations, spanning almost the totality of the world's cultures. Depending on the variety, an onion can be sharp, spicy, tangy, pungent, mild or sweet.
Data from southern European populations showed intake of allium vegetables, including onion are  inversely associated reduced  risk of several common cancers, including breast cancer(22).
 Fisetin, a chemical constituent found in Onion, in prostate cancer, it exerted anti cell profilerative effect as a dual inhibitor of the PI3K/Akt (anti-apoptosis and increased cell proliferation) and the mTOR(regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription) pathways(23). Quercetin, also found in onion, inhibited the prostate cancer line PC-3 through DNA fragmentation and protein expressions of Bcl-2, Bcl-xL, Bax and caspase-3 (cell apoptosis) pathways(24).

9. Turmeric
Turmeric is a perennial plant in the genus Curcuma, belonging to the family Zingiberaceae, native to tropical South Asia. The herb has been used in traditional medicine as anti-oxidant, hypoglycemic, colorant, antiseptic, wound healing agent, and to treat flatulence, bloating, and appetite loss, ulcers, eczema, inflammations, etc.
In PC-3M prostate cancer cell line, extract from turmeric, showed significant inhibitory effects on anti profilerative ability in PC-3M in clonogenic assays(25). Demethoxycurcumin (DMC), one of mjor chemical constituents found in turmeric, exerted it antitumor effects on prostate cancer cells via AMPK((cellular energy homeostasis))-induced down-regulation of HSP70 (upregulated by and toxic chemicals, particularly heavy metals) and EGFR(over expression of epidermal growth factor receptor  have been associated with a number of cancers)(26)(27). Curcumin, a non-nutritive yellow pigment derived from the turmeric showed a inhibitory effects on the expression of  NF-κB (a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis)correlated with their effects on growth inhibition and apoptosis stimulation in PC-3 cells(28).

10. Ginseng
Ginseng is a slow-growing perennial plants with fleshy roots, the genus Panax, belonging to the family Araliaceae. Depending to the climate where it grows, ginseng can be classified mainly into Panax ginseng Asian ginseng (root), Red ginseng, wild ginseng, American ginseng (root).
In a highly metastatic PC-3M prostate cancer cell line,  Ginsenoside Rg3 (Rg3), a bioactive extract from ginseng, suppressed migration of PC-3M cells by down-regulating AQP1(a molecular water channel protein) expression through p38 (highly expressed in aggressive and invasive cancers)MAPK(Increased MAPK expression and activity in primary human carcinoma) pathway and some transcription factors acting on the AQP1 promoter(29). Ginsenoside 20(S)-Rh2  of Ginsenosides, a main component of ginseng, found to be effective in proliferation inhibition on androgen-dependent and -independent prostate cancer cells(30). Formula of Botanical Supplement-101 (TBS-101), containing Panax ginseng, cranberry, green tea, grape skin, grape seed, Ganoderma lucidum and chamomile showed significant inhibition of tumor growth and invasion in a dose-dependent manner(31).

11. Grape Seed Extract
Grape Seed Extract is the commercial extracts from whole grape seeds containing many concentrations, including vitamin E, flavonoids, linoleic acid, oligomeric proanthocyanidins(OPCs), etc.. The herb has been used in traditional medicine as antioxidant, anti-inflammatory agents and to treat skin wounds with less scarring, allergies, macular degeneration, arthritis, enhance circulation of blood vessels, lower cholesterol, etc.
Grape seed extract (GSE), inhibited HAT(HAT mutations are associated to certain cancers), leading to decreased AR(plays roles in prostate development and cancer (PCa))-mediated transcription and cancer cell growth, and implicate GSE as a novel candidate for therapeutic activity against prostate cancer(32). B2G2 from total GSE, derived from Procyanidin B2 3,3″-di-O-gallate, a Biologically Active Constituent of Grape Seed Extract inhibited cell growth, decreased clonogenicity(colony expansion), and induced cell cycle arrest and apoptotic death, in various human PCa cell lines(33).
In a highly metastatic androgen-independent PC3 prostate cancer, Grape seed extract (GSE),  inhibited DNA-binding activity of the transcription factor nuclear factor kappa B (NFkappaB)(a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis), which in turn decreased NFkappaB-dependent uPA(in tumor invasion and metastasis) transcription(33).

12. Danshen (Salvia miltiorrhiza Bunge)
Dan Shen is also known as Red Sage Root. The bitter and slightly cold herb has been used in TCM as antithrombotic, antihypertonic (lowering blood pressure), antimicrobial, antipyretic, anti-inflammatory, sedative agent and to treat dysmenorrhea, amenorrhea, palpable tumors, angina,restlessness, insomnia, irritability, etc., by enhancing the functions of heart and liver channels.
Tanshinones, a chemical constituent found in Chinese herb Dan Shen, was found to be effective in inhibition of the growth of growth of prostate cancer sell lines, in a dose-dependent manner through cell cycle arrest and apoptosis induction(34)and specially in LNCaP cells more than several androgen-independent PCa cell, through suppression of  prostate cancer growth and androgen receptor(AR) signaling.(35) or through induction of  G1 arrest via activation of p53(tumor antigen) signaling and inhibition of AR in LNCaP cells(36).

13. Ginkgo biloba
Ginkgo biloba is oldest living tree species, genus Ginkgo, belonging to the family Ginkgoaceae, native to China, from temperate zone to subtropical zone and some parts of north America. It has been used in traditional herbal medicine in treating impotence, memory loss,respiratory diseases, circulatory disorders and deafness as well as preventing drunkenness, and bedwetting.
Ginkgetin, isolated from leaves of Ginkgo biloba L, inhibited PC-3 cells in a concentration-dependent manner, through significantly increased the sub-G1(detection of cumulative apoptosis)  DNA contents of cell cycle by activated caspase-3 (mechanisms of apoptosis) and weakened  the expression of survival genes such as Bcl-2, Bcl-xL,(family of regulator proteins that regulate cell death) Survivin (baculoviral inhibitor), and Cyclin D1(regulating cell cycle progression) at protein and mRNA levels(37). Unfortunately, Some reseachers suggested that There were no associations for use of  ginkgo biloba in reduced risk of prostate cabcer(38)(39)

14. Licorice (Glycyrrhiza Glabra)
Licorice (Glycyrrhiza Glabra) also known as sweetwood, is the genus Glycyrrhiza, belonging to the family Fabaceae, native to the Mediterranean and certain areas of Asia. The herb has been used in traditional medicine to treat skin diseases, coughs, constipation, bronchitis, inflammation.
Licochalcone-A, isolated from licorice, induced modest level of apoptosis of androgen-independent PC-3 prostate cancer cells through the cell cycle progression arresting cells in G2/M, accompanied by suppression of cyclin B1 and cdc2(cell division cycle 2)(40). Isoangustone A (IAA) in licorice,  attenuated the growth of prostate cancer cell cultures and xenograft tumors attributed to inhibition of the G1/S phase cell cycle transition and the accumulation of p27(cell cycle inhibitor)(41). Other chemical compound such as Glycyrrhetinic acid found in licorice, in the experiment of prostate cancer cell line DU-145, inhibited proliferation and growth of these cells by inducing apoptosis, through down regulated expression of NF-κB (p65). (42).

15. Peppermint
Peppermint is a hybrid mint with small purple or white flowers and downy leaves, in the genus Mentha, belonging to the family Lamiaceae, native to  Europe. The herb has been used in folk medicine as analgesic, antiseptic, antispasmodic, decongestant, agent and to relieve gas, nausea, and stomach pain due to an irritable bowel, intestinal cramps, or indigestion, infecttion, etc.
essential oils of peppermint exerted its cytotoxic effect against of  prostate cancer (LNCaP) cell lines(43). Menthol, a naturally isolated from peppermint oil, induces cell death in PC-3 cells independent to Ca(2+) influx pathways(44). When combined with 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], the most active form of vitamin D(3), menthol increases an anti-proliferation activity of 1alpha,25(OH)(2)D(3) in LNCaP prostate cancer cells, through evoking the increase in [Ca(2+)](45).

16. Wolfberry
Wolfberry is the common name for the fruit of two very closely related species, the genus of Lycium, belong to family Solanaceae, native to native to southeastern Europe and Asia.
Lycium barbarum polysaccharides (LBPs) in dose and time-dependently inhibited the growth of both PC-3 and DU-145 cells through exhibiting  the breakage of DNA strands of PC-3 and DU-145 cells; and induced apoptosis(46). Extract from Lycium barbarum. showed an inhibited effect against  PC3 cell proliferation(47).

18. Rosemary 
Rosemary is a perennial herb with fragrant, evergreen, needle-like leaves, the genus Rosmarinus, belonging to the family Lamiaceae. Its fresh and dried leaves has been used frequently in traditional Mediterranean cuisine and as flavor foods while barbecuing.
Polyphenols isolated from rosemary, inhibited prostate cancer cell through targeting multiple signaling pathways involved in cell cycle modulation and apoptosis(48). Carnosic acid (CA), a polyphenolic diterpene, isolated from rosemary, inhibited apoptosis of PC-3 cells, by activation of PP2A(play critical roles in cell cycle and apoptosis) through modulation of Akt/IKK/NF-κB pathway(49).

Taking altogether, The above herbs have shown effectively in reduced risk and treatments of prostate cancer, through induced apoptosis, exhibited anti proliferation of prostate cancer cell line in cell cycle arrest, down regulation of pro cell growth pathways, etc.. Please consult with your doctor or related field specialist before applying.
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References
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(3) Aloe-emodin suppresses prostate cancer by targeting the mTOR complex 2 by Liu K, Park C, Li S, Lee KW, Liu H, He L, Soung NK, Ahn JS, Bode AM, Dong Z, Kim BY, Dong Z.(PubMed)
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(31) The effect of a novel botanical agent TBS-101 on invasive prostate cancer in animal models by Evans S, Dizeyi N, Abrahamsson PA, Persson J.(PubMed)
(32) Grape seed extract regulates androgen receptor-mediated transcription in prostate cancer cells through potent anti-histone acetyltransferase activity by Park SY, Lee YH, Choi KC, Seong AR, Choi HK, Lee OH, Hwang HJ, Yoon HG.(PubMed)
(32) Procyanidin B2 3,3″-di-O-gallate, a Biologically Active Constituent of Grape Seed Extract, Induces Apoptosis in Human Prostate Cancer Cells Via Targeting NF-κB, Stat3, and AP1 Transcription Factors by Tyagi A, Raina K, Shrestha SP, Miller B, Thompson JA, Wempe MF, Agarwal R, Agarwal C.(PubMed)
(33) NFkappaB-dependent regulation of urokinase plasminogen activator by proanthocyanidin-rich grape seed extract: effect on invasion by prostate cancer cells by Uchino R, Madhyastha R, Madhyastha H, Dhungana S, Nakajima Y, Omura S, Maruyama M.(PubMed)
(34) Bioactive tanshinones in Salvia miltiorrhiza inhibit the growth of prostate cancer cells in vitro and in mice by Gong Y, Li Y, Lu Y, Li L, Abdolmaleky H, Blackburn GL, Zhou JR.(PubMed)
(35) Tanshinones from Chinese medicinal herb Danshen (Salvia miltiorrhiza Bunge) suppress prostate cancer growth and androgen receptor signaling by Zhang Y, Won SH, Jiang C, Lee HJ, Jeong SJ, Lee EO, Zhang J, Ye M, Kim SH, Lü J.(PubMed)
(36) Activation of p53 signaling and inhibition of androgen receptor mediate tanshinone IIA induced G1 arrest in LNCaP prostate cancer cells by Won SH, Lee HJ, Jeong SJ, Lü J, Kim SH.(PubMed)
(37) Ginkgetin induces apoptosis via activation of caspase and inhibition of survival genes in PC-3 prostate cancer cells by You OH, Kim SH, Kim B, Sohn EJ, Lee HJ, Shim BS, Yun M, Kwon BM, Kim SH.(PubMed)
(38) Specialty supplements and prostate cancer risk in the VITamins and Lifestyle (VITAL) cohort by Brasky TM, Kristal AR, Navarro SL, Lampe JW, Peters U, Patterson RE, White E.(PubMed)
(39) Ginkgo biloba and risk of cancer: secondary analysis of the Ginkgo Evaluation of Memory (GEM) Study by Biggs ML, Sorkin BC, Nahin RL, Kuller LH, Fitzpatrick AL.(PubMed)
(40) Licochalcone-A, a novel flavonoid isolated from licorice root (Glycyrrhiza glabra), causes G2 and late-G1 arrests in androgen-independent PC-3 prostate cancer cells by Fu Y, Hsieh TC, Guo J, Kunicki J, Lee MY, Darzynkiewicz Z, Wu JM.(PubMed)
(41) CDK2 and mTOR are direct molecular targets of isoangustone A in the suppression of human prostate cancer cell growth by Lee E, Son JE, Byun S, Lee SJ, Kim YA, Liu K, Kim J, Lim SS, Park JH, Dong Z, Lee KW, Lee HJ.(PubMed)
(42) 18α-glycyrrhetinic acid targets prostate cancer cells by down-regulating inflammation-related genes by Shetty AV, Thirugnanam S, Dakshinamoorthy G, Samykutty A, Zheng G, Chen A, Bosland MC, Kajdacsy-Balla A, Gnanasekar M.(PubMed)
(43) Seasonal variation in content, chemical composition and antimicrobial and cytotoxic activities of essential oils from four Mentha species by Hussain AI, Anwar F, Nigam PS, Ashraf M, Gilani AH.(PubMed)
(44) Menthol regulates TRPM8-independent processes in PC-3 prostate cancer cells by Kim SH, Nam JH, Park EJ, Kim BJ, Kim SJ, So I, Jeon JH.(PubMed)
(45) Menthol Enhances an Antiproliferative Activity of 1alpha,25-Dihydroxyvitamin D(3) in LNCaP Cells by Park EJ, Kim SH, Kim BJ, Kim SY, So I, Jeon JH.(PubMed)
(46) Lycium barbarum polysaccharides induce apoptosis in human prostate cancer cells and inhibits prostate cancer growth in a xenograft mouse model of human prostate cancer by Luo Q, Li Z, Yan J, Zhu F, Xu RJ, Cai YZ.(PubMed)
(47) [Extraction and isolation of active component for inhibiting PC3 cell proliferation in vitro from the fruit of Lycium barbarum L].[Article in Chinese] by Liu XL, Sun JY, Li HY, Zhang L, Qian BC.(PubMed)
(48) Polyphenols from the Mediterranean herb rosemary (Rosmarinus officinalis) for prostate cancer. by Petiwala SM, Puthenveetil AG, Johnson JJ.(PubMed)
(49) Carnosic acid modulates Akt/IKK/NF-κB signaling by PP2A and induces intrinsic and extrinsic pathway mediated apoptosis in human prostate carcinoma PC-3 cells by Kar S, Palit S, Ball WB, Das PK.(PubMed)

Breast Cancer in herbs' Point of View

 By Kyle J. Norton (Draft article)

Epidemiological studies. linking herbal medicine in reduced risk of  breast cancer have produced inconstant results. It may be caused by agendas of the originated sources, length of time or following guide lines loosely.  Breast cancer widespread in women in Southeast Asian as a result of over 2 decades of economic prosperity has caused major concerns in the governments and scientific communities. Emerged suggestions in searching effective treatments in herbal medicine are ongoing, but discover an effective prevention and treatment with little or no side effects has proven difficulty. According to statistic, one in 8 women will be diagnosed to carry some breast cancer tissues sometimes in their life time. Detections of tumor genesis through self observation are still the best approach to cure breast cancer in early stage but reduction of the mortality has not been accounted even with extensively modern technology in the field of diagnosis as well as insurance protection in Western world, needless to say of counties which have little.
Breast cancer (malignant breast neoplasm) is a cancer that starts in the tissues of the breast either from the inner lining of milk ducts (Ductal carcinoma) or the lobules (Lobular carcinoma) that supply the ducts with milk. there is also rare cases that breast cancer starts in other areas of the breast.

1. Anise
Anise is a flowering plant of the species of Pimpinella anisum, genus Pimpinella, belonging to the family Apiaceae native to to Egypt and the Mediterranean region. The popular herb has been used in traditional herbal medicine as fragrance in soaps, oils, and mouth fresheners and stomachic, anti-septic, anti-spasmodic, carminative, digestive, expectorant, stimulant and tonic agent  and to treat head-lice and mites, increase blood pressure, prevent formation of gas in the gastrointestinal tract and menstrual cramps, etc.
Anethole, a major chemical compound in Anise, in MTT and colony formation assays, showed to exhibit anti ER+ and ER breast cancer through suppression of cell survival to cell proliferation and induction of apoptosis in MCF-7 and MDA-MB-231 at an optimal concentration of 1 × 10(-3)M by activating immune response in tumor inhibition(1). Epoxypseudoisoeugenol-2-methyl butyrate isolated from Pimpinella corymbosa, inhibited the proliferation of both MCF-7 and BT-549 cells by blocking NF-kappaB(in inflammation, immunity, cell proliferation and apoptosis) transcriptional activity through induced cell cycle arrest in G(1)/G(0)(Cell cyle) phase and apoptosis(2). Also in the study of selective estrogen receptor modulators or SERMs, Pimpinella anisum in a series of in vitro,  exhibited antiestrogenic effect on breast cancer cells of MCF-7(3).

2. Burdock
Burdock is plant in the group of biennial thistles, genus Arctium, belonging to the family Asteraceae, native to the Euro. It has been used over thousand of years in Chins and other traditional herbal medicine as a diuretic, diaphoretic, and a blood purifying agent and to treat wounds and infections stomach ulcers and other digestive problems.
 Lignin, a chemical constituent in burdock inhibited MDA-MB-231 cell growth by inducing apoptosis through the cell cycle and cell proliferation (ROS/p38 MAPK) pathway and up regulation of (regulator proteins that regulate cell death) Bcl-2 by enhancing antibody antigens(4)lso, in Arctiin, Burdock inhibited the growth of breast caner cells through down-regulation of  cell cycle progression cyclin D1 protein expression(5). Actiin metabolites found in Burdock in the study by the Fourth Military Medical University, in China, showed an inhibited activity on estradiol-mediated proliferation of MCF-7 cells at a concentration of 10 microM(6).

3. Cascara sagrada
Cascara sagrada is a species of buckthorn, genus Rhamnus, belonging to the family Rhamnaceae, native to western North America, it's bark has been used in traditional medicine for gastrointestinal support. and it is thought to have a laxative and natural cleansing, etc..
Emodin, a chemical compound in Cascara sagrada, showed either to reverse the multi-drug resistance in MCF-7/Adr cells and down-regulate ERCC1(the repair of DNA) protein expression(7) and suppress  the proliferation of BCap-37 cells, through the decreased Bcl-2 level(regulate cell death), or induced apoptosis of breast cancer cells by increased expression Bax(involved in p53-mediated apoptosis) and cytosolic(liquid found inside cells) cytochrome c(Protein in the inner membrane of mitochondrial)), on a concentration-and time-dependent manner(8), or through disruption (bad translocation) of the mitochondrial signaling pathway in BCap-37 cells(9).

4. Turmeric
Turmeric is a perennial plant in the genus Curcuma, belonging to the family Zingiberaceae, native to tropical South Asia. The herb has been used in trditional medicine as anti-oxidant, hypoglycemic, colorant, antiseptic, wound healing agent, and to treat flatulence, bloating, and appetite loss, ulcers, eczema, inflammations, etc.
Curcumin a common spicy and the well-known chemopreventive agent in Turmeric, inhibited the level of telomerase gene expression(produces vulnerability of cancer cells) in breast cells treated(10).  It synthetic version, an ortho-hydroxy substituted analog of curcumin (BDMC-A) inhibited MCF-7 at a dose equivalent to that of curcumin (30μM) on the modulation of selective anti tumorenegtic markers (intrinsic pathway: p53, Bcl-2, Bax, cyt c, Apaf-1, caspase-9, 3, PARP; extrinsic pathway: FasL, caspase 8) and ROS (reactive oxygen species) mediation(11). In MDA-MB-231 and BT-483 breast cancer cells, curcumin exhibited the anti-proliferation effect, through lowering the expression of cyclin D1(involved in regulating cell cycle progression) and MMP1 mRNA(involved in the breakdown of extracellular matrix in normal physiological processes and disease processes)(12).

5. Basil
Basil is a species of Ocimum basilicumm, belongong to the family Lamiaceae. It has been used in traditinal medicine to treat cold and flu, coughing, calming the stomach, headache, etc..
Hydrophobic and hydrophilic fractions (HB and HL) exhibited anti tumor growth by decreased in basement membrane disintegration, angiogenesis and MMP-2 and MMP-9 activities in in multiple stages of cancer progression(13).Aqueous OG leaf extract in other study, inhibited proliferation, migration, anchorage independent growth, 3D growth and morphogenesis(the biological process of breast cancer) and induction of COX-2 protein(overexpression in breast cancer cells results in increased cell motility and invasion) in breast cancer cells(14).

6. Green Tea
Green tea contains more amount of antioxidants than any drinks or food with the same volume, and is the leaves of Camellia sinensis, undergone minimal oxidation during processing, originated from China. Green tea has been a precious drink in traditional Chinese culture and used exceptional in socialization for more than 4000 thousand years. Because of their health benefits, they have been cultivated for commercial purposes all over the world.
Mushoom G. lucidum extract (GLE) has been used for the promotion of health, longevity and treatment of cancer. Combination of green tea (GTE) enhanced the effect of G. lucidum extract (GLE) in anti breast cancer cells proliferation (anchorage-dependent growth) through  the down-regulation of expression of oncogene c-myc (frequently altered in human cancers) in MDA-MB-231 cells(15). in green tea polyphenols (GTPs), epigallocatechin-3-gallate (EGCG) induced apoptosis, cell cycle arrest and suppresses metastasis in tumor cells(16). In the study of Green tea consumption and breast caner risk in Japanese women, showed a green tea consumption is not associated with a decreased risk of breast cancer(17).

7. Red clover
Red Clover is a short-lived perennial plant, in the genus Trifolium, belonging to the family Fabaceae, native to to Europe, Western Asia and northwest Africa. The herb has been used in traditional medicine as diuretic and liver cleansing agent and to treat cancer, whooping cough, respiratory problems, and skin inflammations, etc.
Formononetin, a major compound in Red clover, inactivated IGF1/IGF1R-PI3K/Akt (tumorenegtic) pathways and decreased cyclin D1 mRNA(regulating cell cycle progression) and protein expression in human breast cancer cells in vitro and in vivo(18) and through Ras inhibited p38MAPK pathway(19). Unfortunately, study of  Soy, red clover, and isoflavones and breast cancer, suggest that red clover may not possess breast cancer-promoting effects(20).

8. Black cohosh
Black cohosh (known as both Actaea racemosa and Cimicifuga racemosa), a member of is a perennial plant, belonging to the family buttercup, native to North America. The herb has been ised ti herbal medicine to treat symptoms of menopause, premenstrual syndrome (PMS), painful menstruation, acne, osteoporosis, and for starting labor in pregnant women.
Triterpene glycoside actein from black cohoch showed to inhibit the growth of human breast cancer cells and induced a dose dependent release of calcium into the cytoplasm(fluid protoplasm) by altering the activity of the ER(endoplasmic reticulum) IP3(messenger) receptor and Na,K-ATPase(enzyme pumps sodium out of cells)(21). In Female Sprague-Dawley rats treated with an extract of black cohosh enriched in triterpene glycosides (27%), showed an inhibition of fibroadenomas by reduced Ki-67 and cyclin D1 protein expression.(22).

9. Echinacea
Enchinanea also known as purple coneflowers, is a flowering plant of the genus Enchinanea, belonging to the family Asteraceae, native to eastern and central North America. The herb has been used in traditional and herbal medicine to treat or prevent colds, flu, infections by stimulating the immune function, etc..
Cynarine, a chemical compound in Enchinanen affected cell proliferation with properties of proliferative activity on HeLa cells, but antiproliferative activity on MCF-7 cells(23).

10. Parsley
Parsley (Petroselinum crispum) is a biennial flowering plant, genus Petroselinum, belonging to the family Apiaceae, native to the Mediterranean region of southern Europe. The herb has been used in traditional medicine as diuretic agent, and to release spasms, reduce inflammation, clear toxins, enhance the digestion and stimulate uterus, regulate menstrual cycle, treat edema, etc..
Parley alcoholic seed extract (PSA) and seed oil (PSO) of Petroselinum sativum significantly reduced cell viability, and altered the cellular morphology of MCF-7 cells in a concentration dependent manner(24). Carnosol found in parsley, and others herbs such as rosemary, sage, targeted multiple deregulated pathways associated with inflammation and cancer(25). 

11. Rosemary
Rosemary is a perennial herb with fragrant, evergreen, needle-like leaves, the genus Rosmarinus, belonging to the family Lamiaceae. Its fresh and dried leaves has been used frequently in traditional Mediterranean cuisine and as flavor foods while barbecuing. Rosnary has been used in traditional medicine as an antiseptic, antioxidant, and antispasmodic agent to treat circulatory problem, eczema, rheumatism, muscle pain, etc.
Carnosic acid, showed to inhibit proliferation of ER-negative human breast cancer cells and induces G1 cell cycle arrest(26). Other in the study of rosemary extract, carnosol, carnosic acid, ursolic acid, and rosmarinic acid suppressed the development of tumors in several organs including breasts(27). In MDA-MB-231, Rosmarinus officinalis had superior antiproliferative effect without induced toxicity(28).

12. Peppermint
Peppermint is a hybrid mint with small purple or white flowers and downy leaves, in the genus Mentha, belonging to the family Lamiaceae, native to to Europe. The herb has been used in folk medicine as analgesic, antiseptic, antispasmodic, decongestant, agent and to relieve gas, nausea, and stomach pain due to an irritable bowel, intestinal cramps, or indigestion, infecttion, etc.
Dried aqueous extractsform Mentha piperita (ExMp) showed cytotoxicity, against MCF-7 with the least toxicity(29).

13. Thyme
Thyme is a  genus of Thymus, belonging to the family Lamiaceae, native to Europe and North Africa. The herb has been used in flok nedicine to treat  bronchitis, whooping cough, sore throat, colic, arthritis, upset stomach, stomach pain (gastritis), diarrhea, bedwetting, etc..
Thyme extract exhibited significant cytotoxicity and apoptopsis in breast cancer cells (MCF-7 and MDA-MB-231)(30)(31). In the study in comparison of some herbs for their effects in human prostate carcinoma cell (PC-3), human lung carcinoma (A549) and human breast cancer (MCF-7) cell lines, thyme essential oil exhibited the strongest cytotoxicity towards the above three human cancer cells(32).

14. Garlic
Garlic (Allium sativum) is a species in the onion genus, belonging to family Amaryllidaceae, native to central Asia. It has been used popularly in traditional and Chinese medicine in treating common cold and flu to the Plague, blood pressure cholesterol levels, natural antibiotic, etc..
In a case-control study of 345 patients with dietary history questionnaire consisted of a self-administered food frequency questionnaire, showed breast cancer risk was shown to decrease as increased consumption of  garlic and onions(33). Aged garlic extract (AGE) and two of its components, S-allylcysteine (SAC), and S-allyl-mercaptocysteine (SAMC) and breast cancer cells MCF-7 and MCF-7(ras), showed anti-proliferative response due to the alteration in glutathione(antioxidants) level without significant concurrent changes in the glutathione metabolizing enzymes(34). In a breast-cancer cell line (MCF-7), Diallyl disulphide (DADS), a chemical component in garlic, induced phosphatidylserine translocation from the inner to the outer leaflet of the plasma membrane and activates caspase(mechanisms of apoptosis)-3. DADS also modulated the cellular levels of Bax, Bcl-2, Bcl-xL, and Bcl-w (induced apoptosis), in a dose-dependent manner(35).

15. Ginkgo biloba
Ginkgo biloba is oldest living tree species, genus Ginkgo, belonging to the family Ginkgoaceae, native to China, from temperate zone to subtropical zone and some parts of north America. It Has been used in traditional herbal medicine in treating impotence, memory loss,respiratory diseases, circulatory disorders and deafness as well as preventing drunkenness, and bedwetting.
Ginkgo biloba extract (GbE) used conjunction with Tamoxifen (TAM) in GbE in female Sprague-Dawley (SD) rats, showed a slightly beneficial effect on the therapeutic efficacy of TAM in female SD breast cancer bearing rats(36). In the experiment of Ginkgo biloba extract (GBE) effected against MDA-MB-231 (ER-negative) human breast cancer cell line, showed that cytotoxicity effects of GBE in MDA-MB-231 lead to DNA fragmentation at high concentrations (500 and 1,000 μg/ml). activated the Caspase-3 and mRNA levels of apoptosis-related genes (Bcl-2 and Bax)(37). In the study of Antiestrogenic activities of extract of Ginkgo biloba, showed an reduced E2 levels by stimulating the E2 metabolism and inhibiting E2 synthesis and may be considered as a potential alternative to HRT with chemopreventive effects on breast cancer(38).

16. Reishi Mushroom
Reishi mushroom or Lingzhi is a fungal species in the genus Ganoderma, belonging to the family Ganodermataceae, native to Asia. The herb has been use in traditional medicine as anti-caners and anti inflammatory, antioxdant agent and to enhance immune function, treat hepatitis B virus, protect against neuron degeneration, etc..
In Inflammatory Breast Cancer (IBC), with overexpress E-cadherin (plays an important role in the growth, development and the intercellular adhesion of epithelial cells) and the eukaryotic initiation factor 4GI (eIF4GI)(an essential protein that is the target for translational regulation in many cellular processes), Reishi  showed reduced expression of E-cadherin, mTOR(cell proliferation), eIF4G, and p70S6K(cell growth and G1 cell cycle progression) and cell regulation activities(activity of extracellular regulated kinase (ERK1/2))(39). In the study of the same, Reishi showed to inhibited the expression of genes involved in cancer cell survival and proliferation (BCL-2, TERT, PDGFB) of  invasion and metastasis breast cancer cells(MMP-9)(40). An ethanol-soluble and acidic component (ESAC) prepared from Reishi reduced the cell viability of MCF-7 and MDA-MB-231 cells in a concentration-dependent manner with IC(50) of about 100 μg/mL and 60 μg/mL, respectively through effectively mediated G1 cell cycle arrest and exhibited apoptosis(41).

17. Grape Seed Extract
Grape Seed Extract is the commercial extracts from whole grape seeds that contains many concentrations, including vitamin E, flavonoids, linoleic acid, oligomeric proanthocyanidins(OPCs), etc..The herb has been used in traditional medicine as antioxidant, anti-inflammatory agents and to treat skin wounds with less scarring, allergies, macular degeneration, arthritis, enhance circulation of blood vessels, lower cholesterol, etc.
In highly metastatic MDA-MB231 breast cancer cell line, grape seed extract (GSE)showed the effectiveness in cell proliferation and apoptosis through decreased cell migration and invasion, likely by suppressing the β-catenin((plays an important role in the growth, development and the intercellular adhesion of epithelial cells) expression and localization, fascin(cell motility and migration) and NF-κB((a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis) expression(42). Proanthocyanidin, a chemical constituent in grape seeds, showed to suppress  precancerous cellular carcinogenesis through down regulated gene expression of cytochrome-P450 enzymes CYP1A1 and CYP1B1(carcinogenic intermediates)(43). Inbreast cancer cell MCF-7, Grape seed extract inhibited the proliferation and downregulated the gene expression of survivin(baculoviral inhibitor)through through arresting the cell cycle in S phase((synthesis phase for DNA reduplication))(44)

18. Dandelion
Dandelion is a herbaceous perennial plant, genus Taraxacum, beloning to the family Asteraceae, native to temperate regions of the world. It has been used in traditional and herbal medicine to treat gout, eczema, acne, gall bladder, kidney, liver and urinary disorders, hypoglycemia, dyspepsia with constipation, edema, blood pressure and heart weakness, chronic joint, skin diseases, etc.
Aqueous extracts  extracts (DRE), from the mature leaves, flowers and roots of dandelion were investigated for the effects in tumor progression in related processes such as proliferation and invasion, only the crude extract of dandelion leaf (DLE) showed to decrease the growth of MCF-7/AZ breast cancer cells in an ERK(transmits signals from many extracellular agents to regulate cellular processes such as proliferation, differentiation and cell cycle progression)(45)-dependent manner(46).

19. Ginseng
Ginseng is a slow-growing perennial plants with fleshy roots, the genus Panax, belonging to the family Araliaceae. Depending to the climate where it grows, ginseng can be classified mainly into Panax ginseng Asian ginseng (root), Red ginseng, wild ginseng, American ginseng (root). The investigation of Ginseng effects in a cohort of 1,455 breast cancer patients recruited to the Shanghai Breast Cancer Study between August 1996 and March 1998 in Shanghai, China showed that Ginseng use after cancer diagnosis, particularly current use, improved quality of life and reduced risk of death(47). In breast cancer cell line MCF-7 cells, Korean red ginseng (KRG) extracts activated the ERα and ERβ (Estrogen receptor alpha and Beta) through regulating the mRNA levels of estrogen-responsive genes such as pS2 and ESR1 to decreased the protein level of ERα. Also Ginsenoside from Panax notoginseng decreased the survival of breast cancer cells by induction of apoptosis and G1(cell cycle) phase arrest and inhibited the growth of breast cancer xenografts(a graft obtained from breast cancer cells of one species and transplanted to a member of another species) in vivo(49) and inhibited MDM2(an oncoprotein that controls tumorigenesis) expression at both transcriptional(gene expression at the RNA) and post-translational levels in human breast cancer cells with various p53(cellular tumor antigen) statuses(49).

20. Hawthorn
Hawthorn is a shrubs and trees of the genus Crataegus, belonging to the family Rosaceae, native to temperate regions of the Northern Hemisphere in Europe, Asia and North America. The herb has been used in traditional medicine to treat heart disease and symptoms of heart diseases such as irregular heartbeat, high blood pressure, chest pain, hardening of the arteries, etc., circulatory disorders and respiratory illnesses.
In in human MCF-7 breast carcinoma cells, peel polyphenolic extract (HPP) and flesh polyphenolic extract (HFP) from hawthorn fruit although HPP was more effective against MCF-7 cells than HFP, both HPP and HFP interfereed the cell-cycle arrest at the S-phase, and also dose-dependently led to apoptosis of MCF-7 cells via the mitochondrial pathway(inner mitochondrial membrane), by the mechanism of apoptosis of caspase-3 and caspase-9  and the elevation of intracellular ROS(reactive oxygen species) production(50).

21. Licorice (Glycyrrhiza Glabra)
Licorice (Glycyrrhiza Glabra) also known as sweetwood, is the genus Glycyrrhiza, belonging to the family Fabaceae, native to the Mediterranean and certain areas of Asia. The herb has been used in traditional medicine to treat treat skin diseases, coughs, constipation, bronchitis, inflammation, arthritis, etc..
Isoliquiritigenin, a flavonoid phytoestrogen from licorice, induced growth inhibition and apoptosis through downregulating multiple key enzymes in AA metabolic network(inflammatory mediators) and the deactivation of anti-apoptosis and increased cell proliferation(PI3K/Akt)  in human breast cancer(51). Licochalcone E (LicE), a phenolic constituent of licorice, in MDA-MB-231 cells inhibited cell migration and invasion and downregulated the expression of proliferative and anti apoptotic pathways and unregulated secretion of cell proliferation inhibitor(52). Ethanol extract of roasted licorice (rLE) found to be effective in inhibition of breast cancer-mediated bone destruction  by suppressing receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast formation in BMMs(bone marrow-derived macrophages (BMMs)(53).

22, Oregano
Oregano is a perennial herb with aromatic and balsamic flavor, of the genus Origanum in the family Lamiaceae, native to western and southwestern Eurasia and the Mediterranean. The herb has been used in traditional medicine as anti-bacterial, anti-fungal, and anti-viral agent and to treat skin burns, cuts and bruises, sore throat, asthma, colds, coughs and flu, etc.
Carvacrol, a chemical constituent in Oregano showed the anti-tumor effects on human metastatic breast cancer cells, MDA-MB 231 through down regulated the function of mitochondrial membrane potential of the cells(54). In breast cancer cell lines MCF-7, MDA-MB-468 and MDA-MB-231, Origanum acutidens (OA) extracts showed cytotoxicity on all 3 cancer cell lines through expression of Annexin-positive cells level in OA-treated cell lines and caspase-7 (transduction pathways of apoptosis, necrosis and inflammation) protein and TUNEL-positive (indication of apoptosis and accidental cell death) cells(55). In the investigation of essential oil from oregano leaves (Origanum compactum), showed that ethyl acetate extract (30 mg/L) and ethanol extract (56 mg/L) are effective in ambition against human breast cancer cells (MCF7)(56).

23. Rhubarb
Rhubarb is a small flower grouped with large compound leafy in the the genus Rheum, belonging to the family Polygonaceae. The herb has been used in traditional medicine as laxative agent, reduce inflammation and treat diarrhea, dysentery blood clots, tumor red and painful eyes abdominal-distention and/or pain blood in stool hemorrhoidal bleeding urination: burning sensation, absence of menses, etc.
Anthraquinones emodin and aloe-emodin chemical constituents in rhubarb, both inhibited breast cancer cell proliferation by downregulating ER α protein levels in suppressing ER α transcriptional activation(57). Study of combined curcumin and emodin administration showed the inhibition of proliferation (MTT assay), survival (flow cytometry), and invasion (transwell migration assay) of breast cancer cells(58). Rhein, a anthraquinone derivatives, showed antiproliferative and apoptotic effects on both HER2-overexpressing MCF-7 (MCF-7/HER2) and control vector MCF-7 (MCF-7/VEC) cells(59).

24. Cat's claw
Cat's claw found in in the tropical jungles of South and Central America, is a genus Uncaria, belonging to the family Rubiaceae. It has been used in traditional medicine over two thousand years as a tonic, contraceptive, anti-inflammatory and infectious agent, and to treat diarrhea, rheumatic disorders, acne, diabetes, cancer and diseases of the urinary tract, etc..
Extracts and their chromatographic fractions of the Cat's claw, exerted a direct antiproliferative activity on MCF7, with an IC50 of 10 mg/ml and 20 mg/ml, respectively and an antiproliferative effect, with about 90% of inhibition at a concentration of 100 mg/ml(60). Also, pentacyclic oxindole alkaloid mitraphylline isolated from Uncaria tomentosa bark, using cyclophosphamide and vincristine as reference controls, showed to inhibit the growth of both human sarcoma and breast cancer cell lines in a dose-dependent manner(60).

Epidemiologically, the list above has been proven to be effective in reducing risk and treatment of breast cancer through lowering the gene expression of protein in mitochondrial activation of proliferative and anti apoptotic, down regulating tumorgenic and up regulating anticancer pathways. Regardless to their effectiveness, over doses of herbal medicine cause more harm than good. Once again, please consult your herbal specialist before applying and inform your doctor, if you are currently taking any prescribed medicine.
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References
(1) Anethole suppressed cell survival and induced apoptosis in human breast cancer cells independent of estrogen receptor status by Chen CH, deGraffenried LA.(PubMed)
(2) Inhibition of NF-kappaB-mediated transcription and induction of apoptosis in human breast cancer cells by epoxypseudoisoeugenol-2-methyl butyrate by Ma G, Tabanca N, Husnu Can Baser K, Kirimer N, Pasco DS, Khan IA, Khan SI.(PubMed)
(3) Greek plant extracts exhibit selective estrogen receptor modulator (SERM)-like properties by Kassi E, Papoutsi Z, Fokialakis N, Messari I, Mitakou S, Moutsatsou P.(PubMed)
(4) Arctigenin, a dietary phytoestrogen, induces apoptosis of estrogen receptor-negative breast cancer cells through the ROS/p38 MAPK pathway and epigenetic regulation by Hsieh CJ¹, Kuo PL², Hsu YC³, Huang YF⁴, Tsai EM⁵, Hsu YL⁶.(PubMed)
(5) ROS-activated p38 MAPK/ERK-Akt cascade plays a central role in palmitic acid-stimulated hepatocyte proliferation by  Matsuzaki Y, Koyama M, Hitomi T, Yokota T, Kawanaka M, Nishikawa A, Germain D, Sakai T.(PubMed)
(6) ROS-activated p38 MAPK/ERK-Akt cascade plays a central role in palmitic acid-stimulated hepatocyte proliferation by  Xie LH, Ahn EM, Akao T, Abdel-Hafez AA, Nakamura N, Hattori M.(PubMed)
(7) Emodin affects ERCC1 expression in breast cancer cells by Fu JM, Zhou J, Shi J, Xie JS, Huang L, Yip AY, Loo WT, Chow LW, Ng EL.(PubMed)
(8) Emodin-induced apoptosis in human breast cancer BCap-37 cells through the mitochondrial signaling pathway by Huang Z, Chen G, Shi P.(PubMed)
(9) Effects of emodin on the gene expression profiling of human breast carcinoma cells by Huang Z, Chen G, Shi P.(PubMed)
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(44)[Grape seed extract inhibit proliferation of breast cancer cell MCF-7 and decrease the gene expression of survivin].[Article in Chinese] by Chen C, Liu C, Zhang J, Yang Q, Teng F.(PubMed)
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(53)The Inhibitory Effect of Roasted Licorice Extract on Human Metastatic Breast Cancer Cell-Induced Bone Destruction by Lee SK, Park KK, Park JH, Lim SS, Chung WY.(PubMed)
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(57)Emodin and Aloe-Emodin Suppress Breast Cancer Cell Proliferation through ER α Inhibition by Huang PH, Huang CY, Chen MC, Lee YT, Yue CH, Wang HY, Lin H.(PubMed)
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(59)Rhein induces apoptosis in human breast cancer cells by Chang CY, Chan HL, Lin HY, Way TD, Kao MC, Song MZ, Lin YJ, Lin CW.(PubMed)
(60)The antiproliferative effects of Uncaria tomentosa extracts and fractions on the growth of breast cancer cell line by Riva L, Coradini D, Di Fronzo G, De Feo V, De Tommasi N, De Simone F, Pizza C(PubMed)
(60)Cytotoxic effect of the pentacyclic oxindole alkaloid mitraphylline isolated from Uncaria tomentosa bark on human Ewing's sarcoma and breast cancer cell lines by García Giménez D, García Prado E, Sáenz Rodríguez T, Fernández Arche A, De la Puerta R.(PubMed).