Metformin Decreases Circulating Androgen and Estrogen Levels in Nondiabetic Women With Breast Cancer

Campagnoli, C; Berrino, Franco; Venturelli, Elisabetta; Abbà, Chiara; Biglia, Nicoletta; Brucato, Tiziana; Cogliati, Patrizia; Danese, Saverio; Donadio, Michela; Zito, Gianna; Pasanisi, Patrizia

doi:10.1016/j.clbc.2013.08.012

Cited by 53 publications

(43 citation statements)

References 58 publications

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“…Previous studies have reported that women treated with metformin (1,500 mg/day) exhibit a significant reduction in E2 levels (-38%; P= 0.02) and a borderline significant reduction in estrone (-10%; P=0.06) (21). Similar results were obtained in a randomized study in obese postmenopausal female patients with a history of polycystic ovary syndrome and/or insulin resistance (34); treatment with metformin (2,000 mg/day) resulted in a significant reduction in E2 levels (-27%).…”

Section: Discussionmentioning

confidence: 92%

Role of metformin in inhibiting estrogen-induced proliferation and regulating ERα and ERβ expression in human endometrial cancer cells

Zhang

Zhou

et al. 2017

Oncology Letters

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Abstract. Diabetes mellitus (DM) is an important factor that contributes to the development of type I endometrial cancer (EC). Previous studies have demonstrated that metformin decreases mortality and risk of neoplasms in patients with DM. Since estrogen and estrogen receptor (ER) expression has been associated with the development of EC, the present study aimed to investigate the effects of metformin on cell proliferation and ER expression in EC cell lines that are sensitive to estrogen. The viability and proliferation of Ishikawa and HEC-1-A cells were measured following treatment with metformin and/or a 5' AMP-activated protein kinase (AMPK) inhibitor (compound C) with or without treatment with estradiol (E2). In addition, the levels of ERα, ERβ, AMPK, ribosomal protein S6 kinase β-1 (p70S6K), myc proto-oncogene protein (c-myc) and proto-oncogene c-fos (c-fos) were measured following treatment. Metformin significantly decreased E2-stimulated cell proliferation; an effect that was rescued in the presence of compound C. Metformin treatment markedly increased the phosphorylation of AMPK while decreasing p70S6K phosphorylation, indicating that metformin exerts its effects through stimulation of AMPK and subsequent inhibition of the mammalian target of rapamycin (mTOR) signaling pathway. In addition, metformin significantly inhibited ERα expression while increasing ERβ expression, whereas treatment with compound C reversed these effects. Reverse transcription-quantitative polymerase chain reaction analysis demonstrated that c-fos and c-myc expression were attenuated by metformin, an effect that was rescued in the presence of compound C. Therefore, metformin regulates the expression of ERs, and inhibits estrogen-mediated proliferation of human EC cells through the activation of AMPK and subsequent inhibition of the mTOR signaling pathway. IntroductionEndometrial cancer (EC) is the fourth most common cancer in women worldwide and is the most common type of gynecological cancer (1). Patients with high estrogen levels are at increased risk of developing EC since estrogen exhibits growth-promoting properties in EC cells. Thus, estrogen serves as a tumor initiator, since it directly induces DNA mutations in tumor-suppressor genes and oncogenes (2). Upon binding to its receptor, estrogen triggers the transcription of a number of genes. There are two classes of estrogen receptor (ER), ERα and ERβ, which are encoded by the estrogen receptor 1 (ESR1) and ESR2 genes, bind to the same estrogen response elements (EREs) and regulate similar sets of genes (3). However, during the early stages of EC, the expression of ERα is increased compared with that of ERβ (4,5), which activates ERα upon estradiol (E2) binding. This stimulates the expression of estrogen target genes and leads to enhanced proliferation of the previously transformed cells, while causing additional errors in replication and potentially further DNA mutations (2).Previous studies have demonstrated that EC is associated with a shift in the ratio of the two ER subty...

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Section: Discussionmentioning

confidence: 92%

Role of metformin in inhibiting estrogen-induced proliferation and regulating ERα and ERβ expression in human endometrial cancer cells

Zhang

Zhou

et al. 2017

Oncology Letters

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“…In line with these physiological effects, metformin was found to lower postmenopausal breast cancer risk in some [6, 27] but not all studies [7]. Furthermore, metformin can reduce circulating androgen and estrogen levels [28]. Thus, it is plausible that metformin, by reducing levels of endogenous estrogen and cell proliferating insulin, can reduce MD.…”

Section: Discussionmentioning

confidence: 99%

Diabetes, diabetes treatment, and mammographic density in Danish Diet, Cancer, and Health cohort

Buschard

Thomassen

Lynge

et al. 2016

Cancer Causes Control

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PurposeWe examined whether diabetes and diabetes treatment are associated with MD in a cohort study of Danish women above age of 50 years.MethodsStudy cohort consisted of 5,644 women (4,500 postmenopausal) who participated in the Danish Diet, Cancer, and Health cohort (1993–1997) and subsequently attended mammographic screening in Copenhagen (1993–2001). We used MD assessed at the first screening after the cohort entry, defined as mixed/dense or fatty. Diabetes diagnoses and diabetes treatments (diet, insulin, or oral antidiabetic agents) were self-reported at the time of recruitment (1993–1997). The association between MD and diabetes was analyzed by logistic regression adjusted for potential confounders. Effect modification by menopausal status and body mass index (BMI) was performed by introducing an interaction term into the model and tested by Wald test.ResultsOf 5,644 women with mean age of 56 years, 137 (2.4%) had diabetes and 3,180 (56.3%) had mixed/dense breasts. Having diabetes was significantly inversely associated with having mixed/dense breasts, in both, the crude model (odds ratio; 95% confidence interval: 0.33; 0.23–0.48), and after adjustment for adiposity and other risk factors (0.61; 0.40–0.92). Similar inverse associations were observed for 44 women who controlled diabetes by diet only and did not receive any medication (0.56; 0.27–1.14), and 62 who took oral antidiabetic agents only for diabetes (0.59; 0.32–1.09), while women taking insulin had increased odds of mixed/dense breasts (2.08; 0.68–6.35). There was no effect modification of these associations by menopausal status or BMI.ConclusionsHaving diabetes controlled by diet or oral antidiabetic agents is associated with a decrease in MD, whereas taking insulin is associated with an increase in MD.

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“…Moreover, metformin decreases the serum androgen and estrogen levels in nondiabetic women with breast cancer (108,109). (120).…”

Section: Biological Datamentioning

confidence: 99%

Metformin use and gynecological cancers: A novel treatment option emerging from drug repositioning

Gadducci

Biglia

Tana

et al. 2016

Critical Reviews in Oncology/Hematology

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Metformin Decreases Circulating Androgen and Estrogen Levels in Nondiabetic Women With Breast Cancer

Cited by 53 publications

References 58 publications

Role of metformin in inhibiting estrogen-induced proliferation and regulating ERα and ERβ expression in human endometrial cancer cells

Role of metformin in inhibiting estrogen-induced proliferation and regulating ERα and ERβ expression in human endometrial cancer cells

Diabetes, diabetes treatment, and mammographic density in Danish Diet, Cancer, and Health cohort

Metformin use and gynecological cancers: A novel treatment option emerging from drug repositioning

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