Obesity increases the risk of breast cancer by approximately 50% in postmenopausal women and is also associated with a worse prognosis. Elevated estrogen synthesis by the local mammary epithelia and adipose tissue is thought to be the principal mediator of breast tumorigenesis in this population, which primarily develops estrogen receptor alpha (ERα) positive breast cancer. However, the elevated levels of free insulin-like growth factor 1 (IGF-1) that accompany obesity are also thought to play a role. IGF-1 has significant tumorigenic effects in the breast and also regulates aromatase, the key enzyme in the conversion of androgens to estrogen. Consequently, we hypothesized that obesity increases the risk of postmenopausal breast cancer via growth factor-induced aromatase expression and/or activity in the local mammary tissue. We have previously shown that MMTV-Wnt-1 mammary tumors from obese ovariectomized mice express higher levels of aromatase in comparison to tumors from lean ovariectomized mice. To examine the molecular pathways responsible for this effect, we have utilized an in vitro model of obesity in which ERα positive MCF-7 breast cancer cells were exposed to human sera obtained from postmenopausal women and pooled by BMI category. Our data indicates that exposure to obese (BMI ≤ 30 kg/m2) human serum stimulates greater aromatase expression in comparison to control (BMI: 18.5-24.9 kg/m2). This is coupled with enhanced ERα activity when exogenous androgen is present, indicating that the increased aromatase expression results in greater estrogen production. Obese human sera also activates MCF-7 cells’ Akt pathway to a greater degree than control, while MCF-7 cells expressing a constitutively active Akt demonstrate higher levels of aromatase expression in comparison to MCF-7 cells. This suggests that circulating growth factors in the obese sera, like IGF-1, may induce elevated aromatase expression via the downstream PI3K/Akt pathway. To expand on our findings, we plan to assess whether treatment with PI3K/Akt pathway inhibitors eliminates the difference in MCF-7 cells’ aromatase expression following exposure to obese versus control sera. We will also examine how inhibition of the PI3K/Akt pathway affects ERα activity in sera-exposed MCF-7 cells. Through elucidation of the signaling pathways responsible for obesity's upregulation of local aromatase expression, we ultimately hope to develop rational and effective chemopreventive and chemotherapeutic regimens for the high-risk obese postmenopausal population.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3071. doi:1538-7445.AM2012-3071