Abstract P5-05-03: Obesity drives breast cancer progression through estrogen dependent and independent mechanisms
Authors: Wellberg EA , Johnson SJ , Jacobsen BM , Anderson SM , Sartorius CA , MacLean PS , Kabos P 
Published: February 2018

Background: More than 200,000 women are diagnosed with breast cancer each year and 75% develop estrogen receptor positive (ER+) tumors. Obesity is an independent risk factor for the development of ER+ breast cancer, particularly after menopause, and affects 40% of US women. Obese women are more likely to be diagnosed with advanced tumors, lymph node involvement, and less likely to respond to endocrine therapy versus lean women. Mechanisms underlying the increased risk and worse prognosis of obese women are poorly understood. The dogma in the field states that estrogen production is the main contributor to obesity-associated ER+ breast cancer. We show that this is not always the case. Given the epidemic proportions of obesity in the US, we need better pre-clinical models that will inform focused clinical trials and interventions for patients. In this study, we describe a novel mouse model of obesity and ER+ breast cancer patient-derived xenografts (PDX). Our studies highlight the heterogeneity of responses within the ER+ breast cancer subtype to the obese environment and implicate both estrogen-dependent and independent mechanisms of obesity-associated tumor progression.

Methods: ER+, FGFR1-amplified or non-amplified human tumors were established in ovariectomized lean and obese mice in the presence of high or low estradiol (E2). To simulate the hormonal environment of women on aromatase inhibitors, E2 was removed from half of the mice in each adiposity group and the study was terminated 3 weeks later. Weight gain, body fat percentage, and adipose tissue as well as tumor characteristics were analyzed.

Results: Prior to EWD, obese mice were heavier and had higher body fat percentage than lean mice and also displayed a phenotype of metabolic dysfunction. This trend was accelerated after EWD, with obese mice gaining more weight due to body fat accumulation. Tumors responded in one of two ways: Regardless of FGFR1 amplification, obesity promoted ER+ tumor growth in the presence of low (postmenopausal), but not high (premenopausal) E2. In the presence of low E2, tumor PR levels were higher in obese compared to lean mice, suggesting hyperactive ER signaling. In FGFR1-amplified tumors, obesity promoted tumor growth after EWD. In addition, EWD induced excess fat deposition in visceral depots in both lean and obese mice; however, obese mice also gained fat in mammary adipose depots. Mammary fat pad mass and rate of post-EWD weight gain directly correlated with adipose FGF1 levels. Tumors from obese mice had higher levels of phosphorylated FGFR1, without changes in total FGFR1, compared to lean mice.

Conclusions: Utilizing a unique PDX model system, we show that obesity promotes tumor progression in the presence of low E2, and also after EWD, and identify growth factor receptor signaling as a mediator of these phenotypes. The activation of FGFR1 may underlie increased breast cancer risk and recurrence observed in obese, postmenopausal women.

Citation Format: Wellberg EA, Johnson SJ, Jacobsen BM, Anderson SM, Sartorius CA, MacLean PS, Kabos P. Obesity drives breast cancer progression through estrogen dependent and independent mechanisms [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-05-03.