Folate and Endometrial Cancer

The incidence of endometrial cancer among white women are higher in comparison of black women. According to the statistic, the risk of endometrial cancer among women is 1 in 7000. Every year, about 40,000 women in US are diagnosed with the disease. Women who carry certain mutation genes, such as BRCA1 or the BRCA2 are associated to increased risk of endometrial cancer.

Folate, also known as folic acid, vitamin B9, is a water soluble vitamin, found abundantly in leafy vegetables, citrus fruits, beans, whole grain, etc. The vitamin plays an important role in synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in certain biological reactions, production of red blood cells for anemia prevention.

Epidemiological studies, focusing Folate receptor alpha (FRA) in diagnosis of  risk and  dietary in reduced risk of endometrial cancer have been inconclusive. Folate receptor alpha (FRA)  can be overexpressed by a number of epithelial-derived tumors including ovarian, breast, renal, lung, colorectal, and brain, the study emphasized the correlation of the receptor expression in endometrial cancer showed no significant difference in women with endometrial cancer after chemotherapy(1) but an associated growth advantage, rather than the process of tumorigenesis resulting in aberrant expression of FRA per se.(2). But in  "high risk" endometrial carcinomas, Moderate/strong FRalpha staining was significantly associated with other poor prognostic factors including: advanced stage, nonendometrioid histology and high grade of the diseases(3)
One-carbon metabolism dietary factors, including levels of folate, choline, methionine, vitamin B2, vitamin B6 or vitamin B12, do not effect the endometrial incidence(4). But in Type I and II endometrial cancer study, intake of use of supplements containing folate and vitamins B2, B6, and B12 was associated with an increased risk of type II endometrial cancer.(5). The Folate (FOL) mediated poly-lactide-co-glycolide-polyethylene glycol nanoparticles (FOL-PEG-PLGA NPs) bearing paclitaxel (PTX),  was found to be effective in  indcution of cytotoxicity against HEC-1A cancer cells in vitro and in vivo, through possibly induced apoptosis(6). The joint study of the effects of dietary folate and other methyl-related nutrients, as well as three polymorphisms of MTHFR (677C>T, 1298A>C, and 1793G>A), on endometrial cancer risk among women between the ages of 30 and 69 years in urban Shanghai, China, showed an inverse association of folate intake and risk of endometrial cancer and modufied effects in women with encode gene MTHFR polymorphisms(7).

Taking altogether, without going into reviews, dietary folate may associated to reduced risk and treatment of endometrial cancer, but further studies are necessary to validate its effectiveness with large example size. Overdoses of folate may cause stomach problems, sleep problems, skin reactions, seizures, etc., please make sure you follow the guideline of the Institute of Medicine of the National Academies.

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References
(1) Folate receptor alpha (FRA) expression remains unchanged in epithelial ovarian and endometrial cancer after chemotherapy by Despierre E¹, Lambrechts S, Leunen K, Berteloot P, Neven P, Amant F, O'Shannessy DJ, Somers EB, Vergote I.(PubMed)
(2) Expression of folate receptor-α (FRA) in gynecologic malignancies and its relationship to the tumor type by O'Shannessy DJ¹, Somers EB, Smale R, Fu YS.(PubMed)
(3) Rationale for folate receptor alpha targeted therapy in "high risk" endometrial carcinomas.

Brown Jones M¹, Neuper C, Clayton A, Mariani A, Konecny G, Thomas MB, Keeney G, Hartmann L, Podratz KC.(PubMed)

(4) One-carbon metabolism factors and endometrial cancer risk by Liu JJ¹, Hazra A, Giovannucci E, Hankinson SE, Rosner B, De Vivo I.(PubMed)
(5) Dietary and supplemental intake of one-carbon nutrients and the risk of type I and type II endometrial cancer: a prospective cohort study by Uccella S¹, Mariani A, Wang AH, Vierkant RA, Robien K, Anderson KE, Cerhan JR.(PubMed)
(6) Improved therapeutic effect of folate-decorated PLGA-PEG nanoparticles for endometrial carcinoma by Liang C¹, Yang Y, Ling Y, Huang Y, Li T, Li X.(PubMed)
(7) Dietary folate intake, MTHFR genetic polymorphisms, and the risk of endometrial cancer among Chinese women by Xu WH¹, Shrubsole MJ, Xiang YB, Cai Q, Zhao GM, Ruan ZX, Cheng JR, Zheng W, Shu XO(PubMed)

Vitamin B6 and Endometrial Cancer

Kyle J. Norton(Draft Article)

The incidence of endometrial cancer among white women are higher in comparison of black. According to the statistic, the risk of endometrial cancer among women is 1 in 7000. Every year, about 40,000 women in US are diagnosed with the disease. Women who carry certain mutation genes, such as BRCA1 or the BRCA2 are associated to increased risk of endometrial cancer.

Vitamin B6, also known as pyridoxine, is a water soluble vitamin found abundantly in green peas, yams, broccoli, asparagus and turnip greens,Peanuts, sunflower seeds, cashews and hazelnuts, meat, fish etc., with functions of amino acid, carbohydrate  metabolism, brain health, and liver detoxification, etc.

Epidemiological studies linking vitamin B6 in reduced risk of endometrial cancer have been inconclusive, but the composition of vitamin B6 and other micro nutrient have found to be effective in some studies. One-carbon metabolism in 26 years of follow-up data from the Nurses' Health Study, do not appear to influence endometrial cancer incidence but showed protective effect for women with MTHFR 677 TT or MTHFR 1298 CC genotype(1) and a case of case-control study in Greece, indicated that intkae of Retinol, nicotinic acid, vitamin B- 6, and riboflavin  were  inversely associated with the disease(2).
But in a study between 1997 and 2003, 1,204 newly diagnosed endometrial cancer cases and 1,212 controls recruited among women between the ages of 30 and 69 years in urban Shanghai, China, showed dietary intake of vitamin B6 was not related to risk of endometrial cancer for women with enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), encoded by the MTHFR gene(3). Due to small size of some studies, some researchers suggested that large example size and multi centers studies are necessary to validate the effectiveness of any micro nutrient in endometrial cancer risk.

Taking altogether, without going into reviews, the composition of vitamin B6 and other micro nutrients may be effective in reduced risk and treatment of endometrial cancer. Over doses may induced the symptoms of difficulty coordinating movement, numbness, sensory changes, etc., please make sure you follow the guideline of the Institute of Medicine of the National Academies.

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References
(1) One-carbon metabolism factors and endometrial cancer risk by Liu JJ¹, Hazra A, Giovannucci E, Hankinson SE, Rosner B, De Vivo I.(PubMed)
(2)Diet in relation to endometrial cancer risk: a case-control study in Greece by Petridou E¹, Kedikoglou S, Koukoulomatis P, Dessypris N, Trichopoulos D.(PubMed)

(2) Dietary folate intake, MTHFR genetic polymorphisms, and the risk of endometrial cancer among Chinese women by Xu WH¹, Shrubsole MJ, Xiang YB, Cai Q, Zhao GM, Ruan ZX, Cheng JR, Zheng W, Shu XO.(PubMed)

Vitamin B2 and Endometrial Cancer

Kyle J. Norton (Draft Article)

Depending to the stage and grade of the cancer, chemotherapy such as Doxorubicin, Cisplatin. Paclitaxel, Carboplatin, Topotecan may be necessary after surgery with certain side effects. Although epidemiological studies focusing the effective of vegetables and fruits in reduced risk and treatment of endometrial cancer with inconclusive results(1)(2)(3)(4), certain Vitamins, through clinical studies have found to be effective in reduced risk and treatment of endometrial cancer with little or no side effect.

Vitamin B2 also known as  Riboflavin, is a water-soluble, yellow-orange organic compound found abundantly in milk, meat, eggs, nuts, enriched flour, green vegetables, etc. The vitamin is essential for normal cellular growth and function and best known for converting energy from protein, fat, and carbohydrates during metabolism and its antioxidant effects in oxidation-reduction reactions.

Epidemiological studies. linking dietary vitamin B2 in reduced risk of endometrial cancer have produced inconclusive results. The study of Harvard School of Public Health showed a inverse association of vitamin B2  related to the risk of endometrial cancer in a relatively small size of study(5). the co administration of  riboflavin (45 mg/kg bw/day), niacin (100 mg/kg bw/day) and ascorbic acid (200 mg/kg bw/day) along with tamoxifen (45 mg/kg bw/day), in experimental animals with endometrial cancer bearing rats, exhibited a significant decrease in the activity of glycolytic enzymes and a significant increase in the deficient activities of gluconeogenic enzymes to near normal levels, but not individually(6). Unfortunately, the study of Fu Dan University School of Public Health indicted no significant association was observed for dietary vitamin B1 or vitamin B2 and risk of endometrial cancer, in a population-based case-control study of 1,204 newly diagnosed endometrial cancer cases and 1,212 age frequency-matched controls(7)(8). IN the study of one-carbon metabolism correlated to the incidence of endometrial cancer using 26 years of follow-up data from the Nurses' Health Study, indicated a no association of endometrial cancer risk with dietary levels of folate, choline, methionine, vitamin B2, vitamin B6 or vitamin B1(9).

Taking altogether, without going into reviews, composition administration of vitamin B2  and other micro nutrients such as niacin  and ascorbic acid, but not vitamin B2 itself may be associated in reduced risk and treatment of endometrial cancer. But large example and multi-centers studies are necessary to identify their effectiveness. Over doses for a prolong period may cause symptoms of skin rashes, hypersensitivity, high blood pressure etc., please make sure you follow the guideline of the Institute of Medicine of the National Academies.

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References
(1) Conference on "Multidisciplinary approaches to nutritional problems". Symposium on "Nutrition and health". Cruciferous vegetable intake and the risk of human cancer: epidemiological evidence BY Kim MK, Park JH(PubMed)
(2) Epidemiological studies on brassica vegetables and cancer risk by Verhoeven DT, Goldbohm RA, van Poppel G, Verhagen H, van den Brandt PA(PubMed)
(3) Brassica vegetables and cancer prevention. Epidemiology and mechanisms by van Poppel G, Verhoeven DT, Verhagen H, Goldbohm RA.(PubMed)
(4) Fruits and vegetables and endometrial cancer risk: a systematic literature review and meta-analysis by Bandera EV, Kushi LH, Moore DF, Gifkins DM, McCullough ML(PubMed)(5) Diet in relation to endometrial cancer risk: a case-control study in Greece by Petridou E¹, Kedikoglou S, Koukoulomatis P, Dessypris N, Trichopoulos D(PubMed)
(6) Therapeutic potential of riboflavin, niacin and ascorbic acid on carbohydrate metabolizing enzymes in secondary endometrial carcinoma bearing rats by Sundravel S¹, Shanthi P, Sachdanandam P.(PubMed)
(7) Nutritional factors in relation to endometrial cancer: a report from a population-based case-control study in Shanghai, China by Xu WH¹, Dai Q, Xiang YB, Zhao GM, Ruan ZX, Cheng JR, Zheng W, Shu XO.(PubMed)
(8) Dietary folate intake, MTHFR genetic polymorphisms, and the risk of endometrial cancer among Chinese women by Xu WH¹, Shrubsole MJ, Xiang YB, Cai Q, Zhao GM, Ruan ZX, Cheng JR, Zheng W, Shu XO.(PubMed)

Vitamin E and Endometrial Cancer

The incidence of endometrial cancer among white women are higher in comparison of black women. According to the statistic, the risk of endometrial cancer among women is 1 in 7000. Every year, about 40,000 women in US are diagnosed with the disease. Women who carry certain mutation genes, such as BRCA1 or the BRCA2 are associated to increased risk of endometrial cancer.

Depending to the stage and grade of the cancer, chemotherapy such as Doxorubicin, Cisplatin. Paclitaxel, Carboplatin, Topotecan may be necessary after surgery with certain side effects. Although epidemiological studies focusing the effective of vegetables and fruits in reduced risk and treatment of endometrial cancer with inconclusive results(1)(2)(3)(4), certain Vitamins, through clinical studies have found to be effective in reduced risk and treatment of endometrial cancer with little or no side effect.

Vitamin E, a fat soluble vitamin, consisting eight different variants (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol) with varying levels of biological activity(2), found abundantly in corn oil, soybean oil, margarine, wheat germ oil, sunflower,safflower oils, etc. plays an important role in neurological functions and inhibition of platelet aggregation, regulation of enzymatic activity, free radical scavenger, etc..

Antioxidants in epidemiological evidences, are associated to reduced risk of endometrial cancer caused by DNA damage have been controversal. In dose-response meta-analyse, the study bu suggested that dietary intakes of beta-carotene, vitamin C, and vitamin E from food sources, consisted an inverse relationship of endometrial cancer risk(5)(6). The study association between intakes of selected food groups and nutrients with EC risk among 541 women with histologically confirmed EC and 541 women with an intact uterus and noncancer diagnoses seen at Roswell Park Cancer Institute between 1982 and 1998, indicated that intake of vegetable dietary vitamin E are associated with decreased risk of EC(7)(8)(9). But in the study of Instituto de Biotecnología y de Biomedicina with endometrial cells incubated at several hydrogen peroxide concentrations, alpha-tocopherol included in liposomes (1.6 microg) found to no antioxidant effect was detected in cells in culture(7)


Taking altogether, vitamin E may be effective in reduced risk and treatment of endometrial cancer, but large example size and muticenter studies are necessary to validate its effectiveness. Over doses of vitamin E supplement can cause symptoms of blurred vision, weakness, dizziness, nausea, diarrhea, etc., please make sure you follow the guideline of the Institute of Medicine of the National Academies.

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Use The Revolutionary Findings To Achieve 
Optimal Health And Loose Weight

Ovarian Cysts And PCOS Elimination
Holistic System In Existence That Will Show You How To
Permanently Eliminate All Types of Ovarian Cysts Within 2 Months 

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References
(1) Conference on "Multidisciplinary approaches to nutritional problems". Symposium on "Nutrition and health". Cruciferous vegetable intake and the risk of human cancer: epidemiological evidence BY Kim MK, Park JH(PubMed)
(2) Epidemiological studies on brassica vegetables and cancer risk by Verhoeven DT, Goldbohm RA, van Poppel G, Verhagen H, van den Brandt PA(PubMed)
(3) Brassica vegetables and cancer prevention. Epidemiology and mechanisms by van Poppel G, Verhoeven DT, Verhagen H, Goldbohm RA.(PubMed)
(4) Fruits and vegetables and endometrial cancer risk: a systematic literature review and meta-analysis by Bandera EV, Kushi LH, Moore DF, Gifkins DM, McCullough ML(PubMed)
(5)  Antioxidant vitamins and the risk of endometrial cancer: a dose-response meta-analysis by Bandera EV¹, Gifkins DM, Moore DF, McCullough ML, Kushi LH(PubMed)
(6) Higher intakes of vegetables and vegetable-related nutrients are associated with lower endometrial cancer risks. by Yeh M¹, Moysich KB, Jayaprakash V, Rodabaugh KJ, Graham S, Brasure JR, McCann SE(PubMed)
(7) Higher intakes of vegetables and vegetable-related nutrients are associated with lower endometrial cancer risks by Yeh M¹, Moysich KB, Jayaprakash V, Rodabaugh KJ, Graham S, Brasure JR, McCann SE(PubMed)
(8) Nutritional factors in relation to endometrial cancer: a report from a population-based case-control study in Shanghai, China by Xu WH¹, Dai Q, Xiang YB, Zhao GM, Ruan ZX, Cheng JR, Zheng W, Shu XO.(PubMed)
(9) Intake of selected micronutrients and the risk of endometrial carcinoma by Negri E¹, La Vecchia C, Franceschi S, Levi F, Parazzini F.(PubMed)



(10) Antioxidant activity of N-acetylcysteine, flavonoids and alpha-tocopherol on endometrial cells in culture by Estany S¹, Palacio JR, Barnadas R, Sabes M, Iborra A, Martínez P(PubMed)

Vitamin A and Endometrial Cancer

 Kyle J. Norton

The incidence of endometrial cancer among white women are higher in comparison of black women. According to the statistic, the risk of endometrial cancer among women is 1 in 7000. Every year, about 40,000 women in US are diagnosed with the disease. Women who carry certain mutation genes, such as  BRCA1 or the BRCA2 are associated to increased risk of endometrial cancer.

Depending to the stage and grade of the cancer, chemotherapy such as Doxorubicin, Cisplatin. Paclitaxel, Carboplatin, Topotecan may be necessary after surgery with certain side effects. Although epidemiological studies focusing the effective of vegetables and fruits in reduced risk and treatment of endometrial cancer with inconclusive results(1)(2)(3)(4), certain Vitamins, through clinical studies have found to be effective in reduced risk and treatment of endometrial cancer with little or no side effect.

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.
Epidemiological studies, linking vitamin A in reduced risk of endometrial cancer have been inclusive.
1. Retinols
 The Istituto di Ricerche Farmacologiche Mario Negr study in dietary intake of carotenoids and retinol showed no association of retinols in reduced risk of endometrial cancer(5). In the Ishikawa endometrial cancer cell line, Retinoic acid is a metabolite of Retinol inhibited cell proliferation and the expression of RAR(retinoic acid receptor) alpha, RAR beta, and RAR gamma in the Ishikawa endometrial cancer cell line(6). the University Feinberg School of Medicine study in assessing the roles of RA and the RA agonist (AM580) in the growth of endometrial cancer cells, found that both RA and AM580 markedly inhibited endometrial cancer cell proliferation(7). Fenofibrate, an agonist of PPAR-alpha, potentiated by retinoic acid inhibited G1/S phase progression of endometrial cells through the cell cycle arrest(8). In endometrial carcinoma cells line (RL 95-2), RAs exerted its inhibitory effect on the growth of RL 95-2 cells through the estrogen pathway in estrogen-responsive endometrial cancer cells(9) or by interfering with the epidermal growth factor receptor (EGF-R) signaling pathway(10).

2. Carotenoids(beta-carotene, alpha-carotene, gamma-carotene and beta-cryptoxanthin)
Carotenoids, plant pigments, converted to vitamin A after intake, play an important role in prevention and treatment of some diseases through it antioxidant effects. The Brigham and Women's Hospital and Harvard Medical School, in the study of antioxidants intake and risk of endometrial cancer, found no association between intakes of vitamins A, C, E or carotenoids from foods or supplements and cancer risk(11). In a dose-response meta-analysis, intakes of beta-carotene is associated to an inverse risk of endometrial cancer(12). the Medical University of Białystok study in the study suggested that endometrioid adenocarcinoma may be associated to certain enzymatic defects in carotenoid metabolism in the course of the neoplastic process or some metabolic modifications(13). The population-based case-control study in Shanghai, China of 1,204 newly diagnosed endometrial cancer cases and 1,212 age frequency-matched controls, indicated that dietary macronutrients with endometrial cancer associated to cancer risk may depend on the sources, dietary retinol, beta-carotene may decrease the risk of endometrial cancer(14)(15)

Taking altogether, without going into reviews, vitamin A may be associated to reduced risk and treatment of endometrial cancer through inhibition of cell cycle progression, modification of cells differentiated mechanisms. Overdoses can lead 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) Conference on "Multidisciplinary approaches to nutritional problems". Symposium on "Nutrition and health". Cruciferous vegetable intake and the risk of human cancer: epidemiological evidence BY Kim MK, Park JH(PubMed)
(2) Epidemiological studies on brassica vegetables and cancer risk by Verhoeven DT, Goldbohm RA, van Poppel G, Verhagen H, van den Brandt PA(PubMed)
(3) Brassica vegetables and cancer prevention. Epidemiology and mechanisms by van Poppel G, Verhoeven DT, Verhagen H, Goldbohm RA.(PubMed)
(4) Fruits and vegetables and endometrial cancer risk: a systematic literature review and meta-analysis by Bandera EV, Kushi LH, Moore DF, Gifkins DM, McCullough ML(PubMed)
(5) Dietary intake of carotenoids and retinol and endometrial cancer risk in an Italian case-control study by Pelucchi C¹, Dal Maso L, Montella M, Parpinel M, Negri E, Talamini R, Giudice A, Franceschi S, La Vecchia C.(PubMed)
(6) Expression of retinoic acid receptors in human endometrial carcinoma by Tanabe K¹, Utsunomiya H, Tamura M, Niikura H, Takano T, Yoshinaga K, Nagase S, Suzuki T, Ito K, Matsumoto M, Hayashi S, Yaegashi N(PubMed)
(7) Retinoic acid inhibits endometrial cancer cell growth via multiple genomic mechanisms by Cheng YH¹, Utsunomiya H, Pavone ME, Yin P, Bulun SE(PubMed)
(8) In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer by Saidi SA¹, Holland CM, Charnock-Jones DS, Smith SK(PubMed)
(9) Divergent effects of retinoic acids on the expression of ERalpha and 17beta-hydroxysteroid dehydrogenase type 2 in endometrial carcinoma cells (RL 95-2) by Li XH¹, Li H, Xiao ZJ, Piao YS.(PubMed)
(10) Retinoic acid affects the EGF-R signaling pathway during differentiation induction of human endometrial adenocarcinoma cells by Carter CA¹, Shaw BL(PubMed)
(11) Antioxidant intake and risk of endometrial cancer: results from the Nurses' Health Study by Cui X¹, Rosner B, Willett WC, Hankinson SE(PubMed)
(12) Antioxidant vitamins and the risk of endometrial cancer: a dose-response meta-analysis by Bandera EV¹, Gifkins DM, Moore DF, McCullough ML, Kushi LH.(PubMed)
(13) Dietary carotenoids in normal and pathological tissues of corpus uteri by Czeczuga-Semeniuk E¹, Wołczyński S(PubMed)
(14) Nutritional factors in relation to endometrial cancer: a report from a population-based case-control study in Shanghai, China by Xu WH¹, Dai Q, Xiang YB, Zhao GM, Ruan ZX, Cheng JR, Zheng W, Shu XO.(PubMed)
(15) Intake of selected micronutrients and the risk of endometrial carcinoma by Negri E¹, La Vecchia C, Franceschi S, Levi F, Parazzini F.(PubMed)

Endometrial Cancer In Herbs' Points of View

 Kyle J. Norton(Draft Article)

The incidence of endometrial cancer among white women are higher in comparison to black. According to the statistic, the risk of endometrial cancer among women is 1 in 7000. Every year, about 40,000 women in US are diagnosed with the disease. Women who carry certain mutation genes, such as  BRCA1 or the BRCA2 are associated to increased risk of endometrial cancer.
Depending to the stage and grade of the cancer, chemotherapy such as Doxorubicin, Cisplatin. Paclitaxel, Carboplatin, Topotecan may be necessary after surgery with certain side effects. Although epidemiological studies focusing the effective of vegetables and fruits in reduced risk and treatment of endometrial cancer with inconclusive results(1)(2)(3)(4), certain herbs, through clinical studies have found to be effective in reduced risk and treatment of endometrial cancer with little or no side effect.
Endometrium is the inner lining of the mammalian uterus and very susceptible hormone change, particular to menstrual cycle. Endometrial cancer is a late adulthood cancer defined as a condition of which the cells of the endometrial lining of uterus have growth uncontrollable or become cancerous as a result of the alternation of cells DNA. It's the fourth most common cancer among women overall, after breast cancer, lung cancer, and bowel cancer.

1. Licorice
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, arthritis, etc. In mice study, licorice showed to inhibited the proliferation of endometrial carcinogenesis, through a significant decrease in the COX-2, IL-1alpha and TNF-alpha mRNA expressions(5). On estrogen-related endometrial carcinogenesis in mice, treatment after 2 weeks, licorice inhibited the E2-related endometrial carcinogenesis, through suppression of estrogen-induced c-fos/jun(a variety of physiological functions including cell proliferation and differentiation)-expressions(6).

2. 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 years. Because of their health benefits, they have been cultivated for commercial purposes all over the world.
Catechins. the major polyphenols in green tea, showed to reduced risk reduction of  endometrial cancer(7). Epigallocatechin-3-gallate, Another biological active component of green tea, also
inhibited endometrial cancer cell line (Ishikawa cells) proliferation, through cell cycle arrest, interfered with Akt(role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration.) activation and MAPK(role in complex cellular programs like proliferation, differentiation, development, transformation, and apoptosis) signals, and increased apoptosis signals leading to a controlled caspases(mechanisms of apoptosis), Bcl-2(family of regulator proteins that regulate cell death), Bax(involved in p53-mediated apoptosis) genes and protein expression.(8). In a study of 152 patients with histopathologically diagnosed EEA(endometrial cancer), and 285 healthy women of the control who were matched for age and area of residence with individual cases, showed that green tea have an inverse association to endometrial cancer risk regardless of the presence or absence of factors such as obesity and menopause(9).
 
3. 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.
Curcumin, a major chemical constituent of turmeric, inhibited endometrial cancer proliferation through suppresses JAK-STAT(mechanisms of activation and regulation of this essential signaling cascade) signaling via activation of PIAS-3(Protein inhibitor of activated STAT3), thus attenuating STAT-3(signal transducer and activator of transcription-3 (STAT-3) is constitutively activated in ovarian and endometrial cancers) phosphorylation and tumor cell growth(10). In comparison of the effects of letrozole and curcumin in endometrial cancer in nude mice, treatment of curcumin or letrozole induced apoptosis in endometrial cancer and the composition further enhanced the inhibitory rate in tumor growth(11). In human endometrial carcinoma HEC-1-A cells, curcumin induced apoptosis through down-regulation of Ets-1 and Bcl-2 expression(12)

4. 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.
Allium vegetables have been found in many studies to have an inverse association between the frequency of use of and the risk of several common cancers(13). Purified allicin, a major ingredient of crushed garlic, showed to induced apoptosis through induction of activation of caspases-3, -8 and -9 and cleavage of poly(ADP-ribose) polymerase(14) A multi-centre case-control study of 454 endometrial cancer cases and 908 controls, allium vegetables, including garlic showed a moderate protective effect in reduced risk endometrial cancer(15). But according to the Korea Food and Drug Administration, there was no credible evidence to support a  garlic intake in reduced risk of endometrial cancer(16).

5. Ginger
Ginger (Zingiber officinale) or ginger root is the genus Zingiber, belonging to the family Zingiberaceae, native to Tamil. It has been used in traditional and Chinese medicine to treat dyspepsia, gastroparesis, constipation, edema, difficult urination, colic, etc.
A recent report identified a variety of terpenoids inhibited cancer cell proliferation and metastasis via various mechanisms(17), including inhibition of tumor-induced angiogenesis and of various oncogenic and anti-apoptotic signaling pathways and suppression or nuclear translocation of various transcription factors including nuclear factor kappa B (NF-κB)(18).Terpenoids, a chemical constituent found in the Steam Distilled Extract of Ginger (SDGE) induced apoptosis through activating p53(tumor antigen)(19).

6. 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 the study of the effect of several fractions of 6-yr old fresh ginseng and red ginseng, four semi-synthetic ginsenoside Rh1, Rh2, Rg3 and Rg5, major saponin components in red ginseng,suggested that ginsenoside Rg3, Rg5 and Rh2 shwed anticarcinogensis actively. Rg3, Rg5 and Rh2 are active components in red ginseng prevent cancer either singularly or synergistically(20). Ginsenoside-Rb2 derived from ginseng inhibited proliferation of endometrial cancer cell lines  Ishikawa(21). In precancerous lesions of the esophagus and endometrium, Panax ginseng C.A. Meyer cultivated in Russia, bioginseng, panaxel and panaxel- 5, induced the cytotoxic activity of macrophages in mice, enhanced T-lymphocyte rosette formation in guinea pigs(22).

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.
Synthesized carbamate esters with long aliphatic chains without such atoms from Biochanin A (BCA), a major isoflavone in red clover, suppressed cell proliferation Ishikawa cell line(22). the University of Illinois at Chicago study indicated that the flower head and total above-ground parts extracts exhibited differential estrogenic activity in an Ishikawa (endometrial) cel line and autohydrolytic extracts of above-ground parts contained more isoflavones and had more estrogenic activity in Ishikawa endometrial cells as compared with extracts of flower heads(23) and red clover isoflavones had an antiproliferative effect in the endometrium(24).

7. Scutellaria baicalensis (Baikal Skullcap, Huang Qin)
Baikal Skullcap, also known as Huang Qin in traditional Chinese medicine, is a flower plant of the genus Scutellaria,  belonging to the family Lamiaceae, native to China. The herb has been used to treat jaundice,  hypertension ,
anxiety, headache due to cold or flu, prostate Cancer, breast cancer,  red eyes and sore throat, cough
and asthma.
In endometrial cancer cell lines, high does of Huang Qin significantly inhibition of cell growth but
while lower doses stimulated growth in endometrial cell lines(25). In an estrogen-responsive mouse
tumor cell line, the herb Scutellaria baicalensis, significantly inhibited the proliferation of B-1F
cells(estrogen-responsive mouse tumor cell line B-1F ) in vitro and in vivo, through induction of DNA
fragmentation and morphological changes(26).

8. Fritillaria cirrhose (Chuan Bei Mu)
Fritillaria cirrhose is a bulbous plants in the genus of Fritillaria belonging to the family Liliaceae, native to the Northern Hemisphere. The herb has been used in traditional Chinese medicine  as as antibiotic and to raise blood pressure, stop cough, , increased blood sugar,etc. as it transforms Phlegm, calms cough; clears Heat, dissolves nodules, etc. by enhancing the functions of heart and lung channels.
In the composition study of Scutellaria baicalensis (SB) and Fritillaria cirrhosa (FC), suggested that both herb inhibit the proliferation of endometrial cell line through activation of caspase-3(cell apoptosis) G₀ /G₁ phase cell cycle arrest, down regulation of cyclins D1 and D3(regulating cell cycle progression) and induction of p27(Cell cycle inhibition)(27)

9. Bufalin (Chan Su)
Bufalin is also known as toad venom. The acrid, warm, toxic herb has been used in TCM to food poisoning with stomach pain and bloating, vomiting, diarrhea, fainting, painful and swollen throat and certain types of cancer, including liver cancer, intestine cancer, leukemia, skin cancer etc. as it expels toxins, resolves oedema, calms pain, opens the orifices, etc. by enhancing the functions of heart, kidney and stomach channels. Bufalin, the cardioactive C-24 steroids was found to inhibit the growth of tumors of endometrium through cell cycle arrest, apoptosis, and expression of genes proliferation genes(28). The Oita University Faculty of Medicine study also showed that Cang Su indiced apoptosis through decreased the proportion of cells in the S-phase and increased the proportion in the G0/G1 phases of the cell cycle(29).

11. The compositions Shi-Quan-Da-Bu-Tang or Shimotsu-to
Shi-Quan-Da-Bu-Tang is a composition of RenShen, BaiZhu, FuLing, ShuDiHuang, DangQui, Chuan Xiong, HuanQi and RuGui commonly used in traditional Chinese medicine to treat qi and blood accompanied by yang deficiency and cold manifestations. In endometrial cell line, the composition induced apoptosis of the cancer cells through suppression of the suppression of The expression of ER-alpha mRNA, but not ER-beta mRNA(30). Juzen-taiho-to, consisting a mixture of Shimotsu-to and Shikunshi-to formulas, in mice study showed to exert protective effect against estrogen-related endometrial carcinogenesis(31) through suppression of estradiol-17 beta (E2)-induced expression of c-fos/jun(cell proliferation, differentiation and survival) in uterine corpus and inhibition of N-methyl-N-nitrosourea(a highly reliable carcinogen, mutagen, and teratogen) and E2-induced endometrial carcinogenesis(32).

 Taking altogether, without going into reviews, the above list are found ti be effective in reduced risk and treatnent of endometrial cancer through various expressions and mechanisms including cell cycle arrest, upregulation of induced apopticand  downregulation of proliferative expressions. Large sample size and muticenter studies are necessary with identification of the active principle in order to improve the validation of the clinical trial.


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References
(1) Conference on "Multidisciplinary approaches to nutritional problems". Symposium on "Nutrition and health". Cruciferous vegetable intake and the risk of human cancer: epidemiological evidence BY Kim MK, Park JH(PubMed)
(2) Epidemiological studies on brassica vegetables and cancer risk by Verhoeven DT, Goldbohm RA, van Poppel G, Verhagen H, van den Brandt PA(PubMed)
(3) Brassica vegetables and cancer prevention. Epidemiology and mechanisms by van Poppel G, Verhoeven DT, Verhagen H, Goldbohm RA.(PubMed)
(4) Fruits and vegetables and endometrial cancer risk: a systematic literature review and meta-analysis by Bandera EV, Kushi LH, Moore DF, Gifkins DM, McCullough ML(PubMed)
(5) Preventive effects of glycyrrhizin on estrogen-related endometrial carcinogenesis in mice by Niwa K¹, Lian Z, Onogi K, Yun W, Tang L, Mori H, Tamaya T(PubMed)
(6) Preventive effects of Glycyrrhizae radix extract on estrogen-related endometrial carcinogenesis in mice by Niwa K¹, Hashimoto M, Morishita S, Yokoyama Y, Mori H, Tamaya T(PubMed)
(7) Green tea and green tea catechin extracts: an overview of the clinical evidence by Johnson R¹, Bryant S, Huntley AL.(PubMed)
(8) Antiproliferative and apoptotic effect of epigallocatechin-3-gallate on Ishikawa cells is accompanied by sex steroid receptor downregulation by Park SB¹, Bae JW, Kim JM, Lee SG, Han M(PubMed)
(9) Case-control study of green tea consumption and the risk of endometrial endometrioid adenocarcinoma by Kakuta Y¹, Nakaya N, Nagase S, Fujita M, Koizumi T, Okamura C, Niikura H, Ohmori K, Kuriyama S, Tase T, Ito K, Minami Y, Yaegashi N, Tsuji I(PubMed)
(10) Curcumin suppresses constitutive activation of STAT-3 by up-regulating protein inhibitor of activated STAT-3 (PIAS-3) in ovarian and endometrial cancer cells by Saydmohammed M¹, Joseph D, Syed V(PubMed)
(11) [Inhibiting effect of letrozole combined with curcumin on xenografted endometrial carcinoma growth in nude mice].[Article in Chinese] by Liang YJ¹, Zhang HM, Wu YZ, Hao Q, Wang JD, Hu YL(PubMed)
(12) Curcumin down-regulates Ets-1 and Bcl-2 expression in human endometrial carcinoma HEC-1-A cells by Yu Z¹, Shah DM(PubMed)
(13) Onion and garlic use and human cancer by Galeone C, Pelucchi C, Levi F, Negri E, Franceschi S, Talamini R, Giacosa A, La Vecchia C.(PubMed)
(14) Allicin (from garlic) induces caspase-mediated apoptosis in cancer cells by Oommen S, Anto RJ, Srinivas G, Karunagaran D.(PubMed)
(15) Allium vegetables intake and endometrial cancer risk by Galeone C, Pelucchi C, Dal Maso L, Negri E, Montella M, Zucchetto A, Talamini R, La Vecchia C.(PubMed)
(16) Garlic intake and cancer risk: an analysis using the Food and Drug Administration's evidence-based review system for the scientific evaluation of health claims by Kim JY, Kwon O(PubMed)
(17) Terpenoids: natural products for cancer therapy by Huang M¹, Lu JJ, Huang MQ, Bao JL, Chen XP, Wang YT.(PubMed)
(18) Inhibition of tumor progression by naturally occurring terpenoids by Kuttan G¹, Pratheeshkumar P, Manu KA, Kuttan R.(PubMed)
(18) Terpenoids from Zingiber officinale (Ginger) induce apoptosis in endometrial cancer cells through the activation of p53 by Liu Y¹, Whelan RJ, Pattnaik BR, Ludwig K, Subudhi E, Rowland H, Claussen N, Zucker N, Uppal S, Kushner DM, Felder M, Patankar MS, Kapur A.(PubMed)
(19) Terpenoids from Zingiber officinale (Ginger) induce apoptosis in endometrial cancer cells through the activation of p53 ,by Liu Y¹, Whelan RJ, Pattnaik BR, Ludwig K, Subudhi E, Rowland H, Claussen N, Zucker N, Uppal S, Kushner DM, Felder M, Patankar MS, Kapur A(PubMed)
(20) Anticarcinogenic effect of Panax ginseng C.A. Meyer and identification of active compounds by Yun TK¹, Lee YS, Lee YH, Kim SI, Yun HY(PubMed)
(21) Inhibitory effect of ginsenoside-Rb2 on invasiveness of uterine endometrial cancer cells to the basement membrane by Fujimoto J¹, Sakaguchi H, Aoki I, Toyoki H, Khatun S, Tamaya T.(PubMed)
(22) Chemoprevention of mammary, cervix and nervous system carcinogenesis in animals using cultured Panax ginseng drugs and preliminary clinical trials in patients with precancerous lesions of the esophagus and endometrium by Bespalov VG¹, Alexandrov VA, Limarenko AY, Voytenkov BO, Okulov VB, Kabulov MK, Peresunko AP, Slepyan LI, Davydov VV.(PubMed)
(22) Ester and carbamate ester derivatives of Biochanin A: synthesis and in vitro evaluation of estrogenic and antiproliferative activities by Fokialakis N¹, Alexi X, Aligiannis N, Siriani D, Meligova AK, Pratsinis H, Mitakou S, Alexis MN.(PubMed)
(23) Seasonal variation of red clover (Trifolium pratense L., Fabaceae) isoflavones and estrogenic activity by Booth NL¹, Overk CR, Yao P, Totura S, Deng Y, Hedayat AS, Bolton JL, Pauli GF, Farnsworth NR.(PubMed)
(24) A double-blind randomized study on the effects of red clover isoflavones on the endometrium by Hale GE¹, Hughes CL, Robboy SJ, Agarwal SK, Bievre M(PubMed)
(25) The Chinese herbs Scutellaria baicalensis and Fritillaria cirrhosa target NFκB to inhibit proliferation of ovarian and endometrial cancer cells by Kavandi L¹, Lee LR, Bokhari AA, Pirog JE, Jiang Y, Ahmad KA, Syed V.(PubMed)
(26) Possible mechanism of growth inhibition by Scutellaria baicalensis in an estrogen-responsive mouse tumor cell line by Murashima T¹, Katayama H, Shojiro K, Nishizawa Y(PubMed)
(27) The Chinese herbs Scutellaria baicalensis and Fritillaria cirrhosa target NFκB to inhibit proliferation of ovarian and endometrial cancer cells by Kavandi L¹, Lee LR, Bokhari AA, Pirog JE, Jiang Y, Ahmad KA, Syed V.(PubMed)
(28) Bufalin, a traditional oriental medicine, induces apoptosis in human cancer cells by Takai N¹, Kira N, Ishii T, Yoshida T, Nishida M, Nishida Y, Nasu K, Narahara H.(PubMed)
(29) Bufalin induces growth inhibition, cell cycle arrest and apoptosis in human endometrial and ovarian cancer cells by Takai N¹, Ueda T, Nishida M, Nasu K, Narahara H.(PubMed)
(30)Anti-tumor effects of herbal medicines on endometrial carcinomas via estrogen receptor-alpha-related mechanism by Lian Z¹, Niwa K, Onogi K, Mori H, Harrigan RC, Tamaya T(PubMed)
(31) Preventive effect of Juzen-taiho-to on endometrial carcinogenesis in mice is based on Shimotsu-to constituent by Tagami K¹, Niwa K, Lian Z, Gao J, Mori H, Tamaya T.(PubMed)

(32) Cell proliferation in cancer prevention; effects of preventive agents on estrogen-related endometrial carcinogenesis model and on an in vitro model in human colorectal cells by Mori H¹, Niwa K, Zheng Q, Yamada Y, Sakata K, Yoshimi N.(PubMed)
(33) Apoptotic effects of Tian-Long compound on endometrial adenocarcinoma cells in vitro by Li ZL¹, Morishima S, Tang JT, Otsuki Y.(PubMed)

Endometrial Cancer - the Genes Mutation

Kyle J. Norton(Draft Article)

The incidence of endometrial cancer among white women are higher in comparison of black women. According to the statistic, the risk of endometrial cancer among women is 1 in 7000. Every year, about 40,000 women in US are diagnosed with the disease. Women who carry certain mutation genes, such as  BRCA1 or the BRCA2 are associated to increased risk of endometrial cancer.

Endometrium is the inner lining of the mammalian uterus and very susceptible hormone change, particular to menstrual cycle. Endometrial cancer is a late adulthood cancer defined as a condition of which the cells of the endometrial lining of uterus have growth uncontrollable or become cancerous as a result of the alternation of cells DNA. It's the fourth most common cancer among women overall, after breast cancer, lung cancer, and bowel cancer.

The genes mutation
1. BRCA1 or the BRCA2 gene 
Women who carry the genes BRCA1 or the BRCA2, according to Familial Breast Cancer Research study are associated to risk of endometrial cancer, specialty for  the gene BRCA, but the excessive risk is largely attributable to a history of Tamoxifen use.(1) and in aged group between 45 to 70(2).

2. Mutations in DNA mismatch repair (MMR) genes
Mutations in DNA mismatch repair (MMR) genes affects the DNA repair prowess, elevating endometrial cancer risk, due to the loss of proofreading activity of Polε (3). The University of Oxford, study, indicated that mutation of germline exonuclease domain ((EDMs) of POLE and POLD1 are associated to predispose to endometrial cancer (EC) risk(4), Other study showed that defection in either DNA proofreading or MMR may relate to genomic instability and tumourigenesis(5).

3. Phosphatase and tensin homolog (PTEN)
Mation of Mutations of this gene are aassociated ti the development of many types of cancer, specially in altered gene in estrogen-dependent endometrioid endometrial carcinoma tumors(6)

4. K-ras mutations
K-ras gene are protein product plays an essential function in normal tissue signaling. Mutation of KRAS gene is associated to  the development of many cancers. According to the study by Haukeland University Hospital, KRAS mutations over amplification and expression were presented in 14.7% of primary lesions with no increase in metastatic lesions but in 18% of metastatic lesions. and high KRAS mRNA levels sre associated with aggressive phenotype due to activation of ERK1/2 , (in regulating the malignant potential of cancer cells)(7).According to the study by Kanazawa University, 23% of patients with endometrial cancer carry  a mutation in exon 1 of KRAS(7) and 70% of Mutation in codon 12 of the K-ras gene in Serbian patients(8)

5.  β-catenin mutation
β-catenin plays an important role in dual function protein by regulating the coordination of cell–cell adhesion and gene transcription, Mutation and over expression are associated to increased risk of endometrial cancer(9). The Sapporo Medical University study insisted that alternation of the beta-catenin gene occurs in atypical hyperplasia or cancer, rather than in simple or complex hyperplasia without atypia(structural abnormality in a cell), during endometrial carcinogenesis(10).
In an immunohistochemically analyzed 80 endometrial samples (30 of normal endometrium, 20 of endometrial hyperplasia, and 30 of endometrial cancer), beta-catenin was observed in 30% of endometrial cancer samples(11).

6. Lynch syndrome
Lynch syndrome is an inherited condition with increased  risk of colon and other cancers, caused by a germ line mutation in a mismatch repair gene(12). The risk of Lynch syndrome among endometrial cancer patients is 4.6%(13). In a molecular screening for LS in patients with endometrial cancer  ≤ 70 years of age, the risk of  LS is 6% of cases(14), Inactivation of the mismatch repair genes MSH2 and MSH6 are associated to hereditary non-polyposis colorectal cancer (HNPCC; Lynch syndrome)(15).

Taking altogether, genetic mutation of certain genes are associated with increased risk of endometrial cancer. Fortunately, certain foods and herbs have found to be effective in suppressing the expression and blocking the preoperative mechanism and pathways. Please note that all articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying.
     
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References
(1) The incidence of endometrial cancer in women with BRCA1 and BRCA2 mutations: an international prospective cohort study by Segev Y, Iqbal J, Lubinski J, Gronwald J, Lynch HT, Moller P, Ghadirian P, Rosen B, Tung N, Kim-Sing C, Foulkes WD, Neuhausen SL, Senter L, Singer CF, Karlan B, Ping S, Narod SA; Hereditary Breast Cancer Study Group.(PubMed)
(2) The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study by Beiner ME, Finch A, Rosen B, Lubinski J, Moller P, Ghadirian P, Lynch HT, Friedman E, Sun P, Narod SA; Hereditary Ovarian Cancer Clinical Study Group(PubMed)
(3) A common cancer-associated DNA polymerase {varepsilon} mutation causes an exceptionally strong mutator phenotype, indicating fidelity defects distinct from loss of proofreading by Kane DP, Shcherbakova PV(PubMed)
(4) [Identification and management of HNPCC syndrome (hereditary non polyposis colon cancer), hereditary predisposition to colorectal and endometrial adenocarcinomas].

[Article in French by Olschwang S, Bonaïti C, Feingold J, Frébourg T, Grandjouan S, Lasset C, Laurent-Puig P, Lecuru F, Millat B, Sobol H, Thomas G, Eisinger F.(PubMed)

(5) DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer by Church DN, Briggs SE, Palles C, Domingo E, Kearsey SJ, Grimes JM, Gorman M, Martin L, Howarth KM, Hodgson SV; NSECG Collaborators, Kaur K, Taylor J, Tomlinson IP(PubMed)

(6) Genetics of Endometrial Cancers by Tsuyoshi Okuda,^1,* Akihiko Sekizawa,¹ Yuditiya Purwosunu,^{1, 2} Masaaki Nagatsuka,¹ Miki Morioka,¹ Masaki Hayashi,¹ and Takashi Okai(PubMed)
(7) KRAS gene amplification and overexpression but not mutation associates with aggressive and metastatic endometrial cancer by Birkeland E, Wik E, Mjøs S, Hoivik EA, Trovik J, Werner HM, Kusonmano K, Petersen K, Raeder MB, Holst F, Øyan AM, Kalland KH, Akslen LA, Simon R, Krakstad C, Salvesen HB.(PubMed)
(8) Genetic alterations in SMAD4 and K-ras in Serbian patients with endometrial carcinoma by Nikolic A, Ristanovic M, Perovic V, Trifunovic J, Perovic M, Radojkovic D.(PubMed)
(9) Frequent β-catenin gene mutations in atypical polypoid adenomyoma of the uterus by Takahashi H, Yoshida T, Matsumoto T, Kameda Y, Takano Y, Tazo Y, Inoue H, Saegusa M(PubMed)
(10) Mutation of beta-catenin gene in endometrial cancer but not in associated hyperplasia by Ashihara K, Saito T, Mizumoto H, Nishimura M, Tanaka R, Kudo R.(PubMed)
(11) Nuclear localization of beta-catenin in normal and carcinogenic endometrium by Nei H, Saito T, Yamasaki H, Mizumoto H, Ito E, Kudo R.(PubMed)
(12) Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome by Win AK, Lindor NM, Winship I, Tucker KM, Buchanan DD, Young JP, Rosty C, Leggett B, Giles GG, Goldblatt J, Macrae FA, Parry S, Kalady MF, Baron JA, Ahnen DJ, Marchand LL, Gallinger S, Haile RW, Newcomb PA, Hopper JL, Jenkins MA(PubMed)
(13) Prevalence of Lynch syndrome among patients with newly diagnosed endometrial cancers by Egoavil C, Alenda C, Castillejo A, Paya A, Peiro G, Sánchez-Heras AB, Castillejo MI, Rojas E, Barberá VM, Cigüenza S, Lopez JA, Piñero O, Román MJ, Martínez-Escoriza JC, Guarinos C, Perez-Carbonell L, Aranda FI, Soto JL.(PubMed)
(14) Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer ≤ 70 years by Leenen CH, van Lier MG, van Doorn HC, van Leerdam ME, Kooi SG, de Waard J, Hoedemaeker RF, van den Ouweland AM, Hulspas SM, Dubbink HJ, Kuipers EJ, Wagner A, Dinjens WN, Steyerberg EW.(PubMed)
(15) Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities Michael A. Edelbrock^a,, Saravanan Kaliyaperumal^b, , Kandace J. Williams(Science direct)