Abstract 1003: Extranuclear ERα-mTOR signaling rewires cancer cell metabolism during obesity-associated breast cancer

Abstract

Obesity is a preventable risk factor for post-menopausal ERα-(+) breast cancer. We hypothesized that serum from obese post-menopausal women contain factors that would increase tumorigenicity of breast cancer cells and increase risk of ERα-(+) breast cancer. Using whole metabolite profiling and OLINK biomarker panel of about 400 proteins associated with cancer, inflammation and cardiovascular disease, we identified biomarkers that were differentially present in serum from 50 obese v.s. 50 non-obese postmenopausal women. Next, using in vitro cell based assays as proxy we identified certain free fatty acids (FFAs) as factors from serum that correlate with increased cell proliferation, motility and mTOR activation in ERα(+) breast cancer cells. We performed RNA-Seq, ERα ChIP-Seq and metabolomics analysis in breast cancer cells that are exposed to conditions that mimic serum from obese postmenopausal women. This integrative -omics approach enabled us to uncover ERα and mTOR pathway-dependent metabolic rewiring in breast cancer cells under these conditions. Pathway preferential estrogens (PaPEs), which target ERα and mTOR signaling, were able to block free fatty acid-dependent proliferation of breast cancer cells. In fact, efficient cancer cell killing by PaPEs was achieved only in the presence of FFAs, suggesting a role for obesity-associated metabolic rewiring in providing new vulnerabilities for the breast cancer cells. In summary, we uncovered a novel role for extranuclear-initiated ERα signaling in rewiring breast cancer cell metabolism in response to obesity-associated factors in the serum. Our findings provide a basis for preventing or inhibiting obesity-associated breast cancer by using PaPEs that would exploit new metabolic vulnerabilities of breast tumors in obese postmenopausal women. Citation Format: Zeynep Madak Erdogan, Yiru C. Zhao, Gianluigi Rossi, Kinga Wrobel, Eylem Kulkoyluoglu, Sung Hoon Kim, John A. Katzenellenbogen, Jodi Flaws, Rebecca Smith. Extranuclear ERα-mTOR signaling rewires cancer cell metabolism during obesity-associated breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1003. doi:10.1158/1538-7445.AM2017-1003