Abstract 531: Obesity-associated growth factor signaling upregulates aromatase expression in breast cancer cells
Authors: Bowers Laura W. , De Angel Rebecca , Cavazos David , Hursting Stephen , Brenner Andrew , deGraffenried Linda 
Published: June 2012

According to epidemiological studies, obesity increases the risk of breast cancer by approximately 50% in postmenopausal women. Elevated estrogen synthesis by the adipose tissue and local mammary epithelia is thought to be the principal mediator of breast tumorigenesis in this population, which primarily develops estrogen receptor alpha (ERα) positive breast cancer. However, obesity-associated growth factor and cytokine signaling are also thought to play a role. Specifically, obesity is accompanied by elevated levels of insulin, insulin-like growth factor 1 (IGF-1), and leptin. These all have significant tumorigenic effects in the breast and are known to regulate aromatase, the enzyme that catalyzes the conversion of testosterone to estradiol. 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.

MMTV-Wnt-1 transgenic (Wnt-1 TG) mice, which are predisposed to the development of estrogen receptor positive mammary adenocarcinoma, were ovariectomized to mimic a postmenopausal state. They were then randomized to either a diet-induced obesity (DIO) chow (60% calories from fat) or control chow (10% calories from fat) to produce an obese or lean phenotype, respectively. qPCR analysis revealed that aromatase expression in the mammary tumors of the obese mice was almost four-fold greater than in the controls. 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 treated with sera from C57BL/6 mice fed either the DIO or control diet. Human sera obtained from women involved in a case-controlled clinical trial will be pooled by BMI category and also used to treat the cells. Preliminary data indicates that obese mouse sera activates the PI3K/Akt pathway to a greater degree than lean mouse sera. Our lab has also shown that MCF-7 cells expressing a constitutively active Akt demonstrated 37% greater aromatase expression in comparison to vector-transfected MCF-7 cells. This suggests that circulating growth factors in the obese sera may induce elevated aromatase expression via the PI3K/Akt pathway.

These results will be further explored by measuring aromatase expression and aromatase promoter activity in response to treatment with sera from obese and lean subjects. To determine the role of obesity-associated growth factor and leptin signaling on aromatase expression and activity, we will also add inhibitors to these different pathways with the sera treatment. Through elucidation of the signaling pathways responsible for obesity's upregulation of aromatase, we hope to lay the foundation for future research that could result in an effective chemopreventive regimen for the high-risk obese postmenopausal population.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 531. doi:10.1158/1538-7445.AM2011-531