Effects of estrogen receptor α and β on proliferation of endometrial cancer cells_West China Medical Journal

Authors：

HU Guanli ¹ ,  ZHANG Bei ² , ZHANG Jingbo ² , LIU Jianwei ² , WANG Qing ² , DONG Jie ¹ , MENG Lin ³

1. Clinical College of Xuzhou Medical University, Xuzhou, Jiangsu 221004, P. R. China;
2. Department of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, P. R. China;
3. Department of Obstetrics and Gynecology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P. R. China;

Corresponding?author：

ZHANG Bei, Email: bettyzhang10@163.com

Keywords：

Endometrial cancer; Estrogen receptor α; Estrogen receptor β; Metformin; Cell proliferation

DOI：

10.7507/1002-0179.201901178

Video：

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Objective To explore the role of estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) in estrogen-induced proliferation of endometrial cancer, and explore whether metformin inhibits the proliferation of endometrial cancer cells through ERα and ERβ. Methods Stable transfected Ishikawa cells were constructed by lentivirus. The effects of down-regulated ERα and ERβ on estrogen-induced Ishikawa cell proliferation were detected by methyl thiazolyl tetrazolium assay. The effects of down-regulated ERα and ERβ on estrogen-induced Ishikawa cell cycle were detected by flow cytometry. In addition, quantitative real-time polymerase chain reaction and Western blotting assays were used to detect changes in the expression of cyclinD1 and P21 involved in cell cycle regulation. The effects of down-regulated ERα and ERβ on estrogen-induced Ishikawa cell proliferation were observed by adding metformin to estrogen treatment. Results Down-regulation of ERα inhibited the proliferation and cell cycle of Ishikawa cells (P<0.05). Down-regulation of ERα also inhibited the expression of cyclinD1 and promoted the expression of P21 (P<0.05). Down-regulation of ERα counteracted the effect of estrogen-induced cell proliferation, cell cycle, and the expression changes of cyclinD1 and P21 (P<0.05). Down-regulation of ERβ promoted the proliferation and cell cycle of Ishikawa cells (P<0.05). Down-regulation of ERβ also promoted the expression of cyclinD1 and inhibited the expression of P21 (P<0.05). Down-regulation of ERβ enhanced the effect of estrogen-induced cell proliferation, cell cycle, and the expression changes of cyclinD1 and P21 (P<0.05). Metformin inhibited the proliferation of estrogen-induced Ishikawa cells (P<0.05), while in the down-regulated ERα Ishikawa cells or down-regulated ERβ Ishikawa cells, the inhibition of metformin on Ishikawa cells disappeared (P<0.05). Conclusions ERα may promote estrogen-induced proliferation of endometrial cancer cells, while ERβ may inhibit estrogen-induced proliferation of endometrial cancer cells. In addition, ERα and ERβ may also mediate the inhibitory effect of metformin on endometrial cancer cells.

Citation： HU Guanli, ZHANG Bei, ZHANG Jingbo, LIU Jianwei, WANG Qing, DONG Jie, MENG Lin. Effects of estrogen receptor α and β on proliferation of endometrial cancer cells. West China Medical Journal, 2019, 34(8): 921-927. doi: 10.7507/1002-0179.201901178 Copy

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6.	Su T, Qu JJ, Wang K, et al. Cross-talk between p21-activated kinase 4 and ER alpha signaling triggers endometrial cancer cell proliferation. Oncotarget, 2017, 8(40): 68083-68094.
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9.	Tian WY, Teng F, Zhao J, et al. Estrogen and insulin synergistically promote type 1 endometrial cancer progression. Cancer Biol Ther, 2017, 18(12): 1000-1010.
10.	Rizner TL. Estrogen biosynthesis, phase I and phase II metabolism, and action in endometrial cancer. Mol Cell Endocrinol, 2013, 381(1/2): 124-139.
11.	Hapangama DK, Kamal AM, Bulmer JN. Estrogen receptor beta: the Guardian of the endometrium. Hum Reprod Update, 2015, 21(2): 174-193.
12.	Thomas C, Gustafsson J?. The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer, 2011, 11(8): 597-608.
13.	Li JP, Zhuang QR, Lan XP, et al. PES1 differentially regulates the expression of ER alpha and ER beta in ovarian cancer. IUBMB Life, 2013, 65(12): 1017-1025.
14.	Bardin A, Boulle N, Lazennec G, et al. Loss of ER beta expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer, 2004, 11(3): 537-551.
15.	Ahlin C, Lundgren C, Embretsen-Varro E, et al. High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers. Breast Cancer Res Treat, 2017, 164(3): 667-678.
16.	Ye D, Luo H, Lai ZY, et al. ClC-3 chloride Channel proteins regulate the cell cycle by up-regulating cyclin D1-CDK4/6 through suppressing p21/p27 expression in nasopharyngeal carcinoma cells. Sci Rep, 2016, 6: 30276.
17.	Mahabaleshwarkar R, Liu TL, Mulder H. Comparative effectiveness of metformin dosage uptitration versus adding another antihyperglycemic medication on glycemic control in type 2 diabetes patients failing initial metformin monotherapy: a retrospective cohort study. Popul Health Manag, 2019.
18.	Pernicova I, Korbonits M. Metformin--mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol, 2014, 10(3): 143-156.
19.	Hopkins BD, Pauli C, Xing D, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature, 2018, 560(7719): 499.
20.	Eikawa S, Nishida M, Mizukami S, et al. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci USA, 2015, 112(6): 1809-1814.
21.	Cantrell LA, Zhou C, Mendivil A, et al. Metformin is a potent inhibitor of endometrial cancer cell proliferation--implications for a novel treatment strategy. Gynecol Oncol, 2010, 116(1): 92-98.

1. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin, 2017, 67(1): 7-30.
3. Waqar S, Khan SA, Sarfraz T, et al. Expression of estrogen receptors (ER), progesterone receptors (PR) and HER-2/neu receptors in endometrial carcinoma and their associations with histological types, grades and stages of the tumor. Pak J Med Sci, 2018, 34(2): 266-271.
4. 張巖, 廖秦平, 于麗, 等. 子宮內膜癌細胞雌激素受體亞型的調控和功能的初步研究. 中華婦產科雜志, 2005, 40(8): 558-561.
5. 王志啟, 王建六, 魏麗惠, 等. 子宮內膜癌細胞中細胞膜雌激素受體表達的初步研究. 中華婦產科雜志, 2006, 41(7): 471-475.
6. Su T, Qu JJ, Wang K, et al. Cross-talk between p21-activated kinase 4 and ER alpha signaling triggers endometrial cancer cell proliferation. Oncotarget, 2017, 8(40): 68083-68094.
7. 牛藝潔, 史惠蓉, 謝婭. 二甲雙胍對孕激素耐藥的子宮內膜癌細胞的調節作用. 中華婦產科雜志, 2016, 51(2): 135-140.
8. Zhang JB, Xu H, Zhou XE, et al. Role of metformin in inhibiting estrogen-induced proliferation and regulating ER alpha and ER beta expression in human endometrial cancer cells. Oncol Lett, 2017, 14(4): 4949-4956.
9. Tian WY, Teng F, Zhao J, et al. Estrogen and insulin synergistically promote type 1 endometrial cancer progression. Cancer Biol Ther, 2017, 18(12): 1000-1010.
10. Rizner TL. Estrogen biosynthesis, phase I and phase II metabolism, and action in endometrial cancer. Mol Cell Endocrinol, 2013, 381(1/2): 124-139.
11. Hapangama DK, Kamal AM, Bulmer JN. Estrogen receptor beta: the Guardian of the endometrium. Hum Reprod Update, 2015, 21(2): 174-193.
12. Thomas C, Gustafsson J?. The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer, 2011, 11(8): 597-608.
13. Li JP, Zhuang QR, Lan XP, et al. PES1 differentially regulates the expression of ER alpha and ER beta in ovarian cancer. IUBMB Life, 2013, 65(12): 1017-1025.
14. Bardin A, Boulle N, Lazennec G, et al. Loss of ER beta expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer, 2004, 11(3): 537-551.
15. Ahlin C, Lundgren C, Embretsen-Varro E, et al. High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers. Breast Cancer Res Treat, 2017, 164(3): 667-678.
16. Ye D, Luo H, Lai ZY, et al. ClC-3 chloride Channel proteins regulate the cell cycle by up-regulating cyclin D1-CDK4/6 through suppressing p21/p27 expression in nasopharyngeal carcinoma cells. Sci Rep, 2016, 6: 30276.
17. Mahabaleshwarkar R, Liu TL, Mulder H. Comparative effectiveness of metformin dosage uptitration versus adding another antihyperglycemic medication on glycemic control in type 2 diabetes patients failing initial metformin monotherapy: a retrospective cohort study. Popul Health Manag, 2019.
18. Pernicova I, Korbonits M. Metformin--mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol, 2014, 10(3): 143-156.
19. Hopkins BD, Pauli C, Xing D, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature, 2018, 560(7719): 499.
20. Eikawa S, Nishida M, Mizukami S, et al. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci USA, 2015, 112(6): 1809-1814.
21. Cantrell LA, Zhou C, Mendivil A, et al. Metformin is a potent inhibitor of endometrial cancer cell proliferation--implications for a novel treatment strategy. Gynecol Oncol, 2010, 116(1): 92-98.

West China Medical Journal

Effects of estrogen receptor α and β on proliferation of endometrial cancer cells

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