P4-02-08: Obesity-Induced Aromatase Expression in the Breast Microenvironment Promotes Estrogen Receptor Activity Independent of Circulating Estradiol Levels.

Abstract

Abstract Epidemiological studies indicate that obesity increases the risk of postmenopausal breast cancer by approximately 50%. In the past, researchers have hypothesized that elevated estrogen synthesis by the peripheral adipose tissue may be the principal mediator of breast tumorigenesis in this population, which primarily develops estrogen receptor alpha (ERα) positive breast cancer. However, obesity is also accompanied by an elevation in growth factor and cytokine signaling, and these pathways have been linked to tumorigenesis. In addition, certain growth factor and cytokine family members can promote aromatase expression in both the epithelial and stromal tumor compartments. Consequently, we hypothesized that obesity increases the risk of postmenopausal breast cancer via elevated aromatase expression and/or activity in the local mammary tissue. To test our hypothesis, we investigated how ERa activity in mammary epithelial cells was influenced by adipose stromal cells (ASC) cultured under obesity-associated conditions, including high cell density and exposure to elevated levels of circulating growth factors and cytokines. For the latter condition, sera was obtained from postmenopausal women, pooled by BMI category (lean: 18.5−24.9; obese: ≥30), and applied to the ASC, which were originally derived from women undergoing reduction mammoplasty. High ASC density was achieved via the protocol previously published by Dr. Li. Preliminary data indicated that both elevated cell density and sera from obese postmenopausal women induces greater aromatase expression in ASC, indicating that multiple factors may be contributing to the increased local aromatase expression seen with obesity. We are currently exploring the signaling pathways responsible for obesity's upregulation of ASC aromatase expression and will present these results at the meeting. Intriguingly, exposure to conditioned media from both the high density and obese sera-exposed ASC enhanced ERa activity in MCF-7 mammary epithelial cells, independent from exogenous estradiol but dependent on the presence of androgens, suggesting an important role for the aromatase enzyme in this observation. To expand on this finding, we plan to investigate the effect of ASC conditioned media on different markers of cancer aggression, including proliferation and survival, and assess the degree to which these effects depend on estradiol. Through further examination of obesity's impact on signaling pathways in both the epithelial and stromal tumor compartments, we ultimately hope to identify more effective chemopreventive and therapeutic regimens for the high-risk obese postmenopausal population. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-08.