Abstract A08: A patient-derived xenograft model to study the effects of postmenopausal obesity on endocrine therapy resistance

Introduction: Obesity affects more than one-third of adults in the U.S. and increases the risk for and worsens outcomes of individuals with cancer. Obese women have a greater risk of postmenopausal hormone-receptor positive breast cancer and are more likely to relapse after endocrine therapy. The prevailing dogma is that elevated circulating estrogen, produced by aromatase in abundant adipose tissue, drives breast cancer formation and progression. While estrogen is clearly an important factor in the obesity-breast cancer relationship, increasing the dose of aromatase inhibitors provides no added benefit to obese women with breast cancer. A switch from hormone- to growth factor-dependence has been implicated in the development of endocrine therapy resistance. Hypothesis and Study Objective: We hypothesized that obese, postmenopausal women have elevated growth factor production in adipose tissue, which supports the progression of breast tumors that were previously dependent on estrogen. The purpose of our study was to develop a transplant-competent mouse model of obesity and postmenopausal breast cancer using estrogen receptor (ER) positive breast cancer patient-derived xenografts (PDX) from peri- and postmenopausal women (ages 45-71). Methods: Rag1-null mice on the C57Bl/6 background were fed either a low fat (LFD) or high fat (HFD) diet for 10 weeks. Thermoneutral housing was used to facilitate development of the obese phenotype. Animal weights and percent body fat were monitored. After weight separation (approximately 10 weeks), mice were ovariectomized and implanted with an ER+ estrogen-dependent PDX derived from a 54 year old woman bilaterally into the orthotopic site (inguinal mammary fat pad). Mice were given slow release estrogen pellets and tumor growth was monitored. After 8 weeks of tumor growth, a subset of animals received estrogen withdrawal (EWD) to mimic the menopausal transition. Results: HFD-fed mice weighed more, and had significantly increased body fat percentages, as well as subcutaneous, and gonadal fat pad weights, compared to LFD-fed mice. After EWD, tumors regressed in LFD-fed mice; however, the HFD prevented tumor regression in the absence of estrogen. Circulating estrogen levels in both LFD and HFD EWD groups were not significantly different. Tumor cellularity and Ki67 were greater in HFD- compared to LFD-fed mice in the absence of estrogen. Phospho-protein analysis of tumors suggested increased human epidermal growth factor receptor 2 (HER2) and fibroblast growth factor receptor (FGFR) signaling in HFD-EWD versus LFD-EWD mice. Conclusions: We have developed a novel, transplant-competent mouse model of obesity and menopause using a specialized HFD and thermoneutral housing. Using this model, we determined that HFD supports the growth of a previously estrogen-dependent breast cancer PDX after EWD, potentially through increased signaling through HER2 and FGFR pathways. Our mouse model, in combination with PDX breast tumors, will offer novel insights into the relationships between obesity, menopause, and ER+ breast cancer progression. Citation Format: Elizabeth Wellberg, Britta Jacobsen, Peter Kabos, Paul MacLean, Carol Sartorius. A patient-derived xenograft model to study the effects of postmenopausal obesity on endocrine therapy resistance. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A08.