Chemopreventive effects of metformin on obesity-associated endometrial proliferation

Abstract

Objective Obesity is a significant contributing factor to endometrial cancer risk. We previously demonstrated that estrogen-induced endometrial proliferation is enhanced in the context of hyperinsulinemia and insulin resistance. In this study we investigate whether pharmacologic agents that modulate insulin sensitivity or normalize insulin levels will diminish the proliferative response to estrogen. Study Design Zucker fa/fa obese rats and lean controls were used as models of hyperinsulinemia and insulin resistance. Insulin levels were depleted in ovariectomized rats following treatment with Streptozotocin (STZ), or modulated by metformin treatment. The number of BrdU incorporated cells, estrogen dependent proliferative and anti-proliferative gene expression, and activation of mTOR and Erk1/2 MAPK signaling were studied. A rat normal endometrial cell line RENE1 was used to evaluate the direct effects of metformin on endometrial cell proliferation and gene expression in vitro. Results STZ lowered circulating insulin levels in obese rats and decreased the number of BrdU labeled endometrial cells even in the presence of exogenous estrogen. Treatment with the insulin-sensitizing drug metformin attenuated estrogen-dependent proliferative expression of c-myc and c-fos in the obese rat endometrium compared to untreated controls and was accompanied by inhibition of phosphorylation of the insulin and IGF1 receptors (IRβ/IGF1R) and ERK1/2. In vitro studies indicated metformin inhibited RENE1 proliferation in a dose dependent manner. Conclusion These findings suggest that drugs that modulate insulin sensitivity, such as metformin, hinder estrogen-mediated endometrial proliferation. Therefore, these drugs may be clinically useful for the prevention of endometrial cancer in obese women.

Clinical benefits of metformin in gynecologic oncology

“…Metformin resulted in G1 phase cell cycle arrest, induction of apoptosis and decreased human telomerase reverse transcriptase expression in endometrial cancer cells (50,55). Treatment with metformin attenuates the estrogen-dependent proliferative expression of c-myc and c-fos in the obese rat endometrium, an effect which was accompanied by inhibition of the phosphorylation of insulin and IGF1 receptors, as well as Erk 1/2 (17,55). In vitro studies have indicated that metformin inhibits rat endometrial cell line proliferation and suppresses endometrial cancer cell growth via cell cycle arrest and concomitant autophagy and apoptosis (55,56).…”

“…Although various anticancer effects of metformin have previously been described (1,2,(15)(16)(17)(18)(19)(20)24,25), the suppression of LKB1-mediated mTOR signaling is hypothesized to be the fundamental mechanism underlying these effects. Metformin has been demonstrated to be associated with reduced risk and enhanced overall survival rates of several obesity-associated types of cancer, although variable results have been obtained between studies.…”

“…Metformin, a biguanide frequently used in the treatment of type 2 diabetes, has been demonstrated to exert marked chemopreventative and antiproliferative effects against various types of cancer (1,2,(15)(16)(17)(18)(19)(20). Metformin is able to inhibit cell growth via insulin and non-insulin dependent mechanisms (1,2,(15)(16)(17), while enhancing insulin receptor sensitivity, increasing insulin uptake and therefore reducing systemic insulin levels.…”

“…Metformin is able to inhibit cell growth via insulin and non-insulin dependent mechanisms (1,2,(15)(16)(17), while enhancing insulin receptor sensitivity, increasing insulin uptake and therefore reducing systemic insulin levels. Metformin is also able to inhibit cell proliferation via activation of the growth inhibitory adenosine monophosphate-activated protein kinase (AMPK).…”

CGRRF1 as a novel biomarker of tissue response to metformin in the context of obesity

“…While circulating insulin levels reflect systemic responses to metformin, and are easily measured, additional tissue-specific biomarkers of metformin are necessary to assess metformin response in the endometrium. General markers of proliferation, such as Ki67 and PCNA, have some utility but may not be sufficiently sensitive to reflect tissue response to short-term metformin use [17].…”