Abstract 3927: Obesity induces changes in adipokines profile and activates Akt/mTOR signaling accelerating breast carcinogenesis and tumor growth

Abstract

Abstract Obesity increases the risk of cancer death among postmenopausal women with estrogen receptor-positive (ER+) breast cancer (BC), but the direct evidence for the mechanisms is lacking. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating this epidemiological phenomenon. Transcriptomic profiles of pretreatment biopsies from a prospective cohort of 137 ER+ BC patients were analyzed. Transgenic and an orthotopic/syngeneic obese mouse models were created to phenocopy obese patients and evaluate the effect of obesity on breast carcinogenesis and tumor progression, and to explore further direct mechanisms. We used co-culture system to examine the impact of adipocytes and adipokines on BC cell proliferation. Functional transcriptomic analysis of patients revealed the association of obesity with many of the functional changes linked to cancer hallmarks. Our transgenic and orthotopic/syngeneic obese-mouse models recapitulated the functional transcriptomic landscape of obesity-associated changes seen in human patients and demonstrated the role of the Akt/mTOR pathway in obesity-induced breast carcinogenesis and tumor progression. Metformin and everolimus can suppress obesity-induced adipokines secretion and breast tumor formation and growth. An in vitro co-culture model revealed that adipocyte-secreted adipokines (e.g., TIMP-1) regulate adipocyte-induced BC cell proliferation and invasion. Metformin suppress adipocytes-induced cell proliferation and adipocytes-secreted adipokines in vitro. In conclusion, the patients' data provided evidence for the mechanistic involvement of adipokines in addition to estrogen, insulin and IGF-1 signaling in the link between obesity and ER+ BC. Our animal experiments provide strong evidence for the role of obesity on the accelerated breast carcinogenesis and obesity-induced tumor growth by activation of the Akt/mTOR signaling. Metformin and everolimus may be use as alternatives therapeutic interventions for BC patients with obesity. Citation Format: Enrique Fuentes-Mattei, Guermarie Velazquez-Torres, Liem Phan, Fanmao Zhang, Ping-Chieh Chou, Ji-Hyun Shin, Hyun-Ho Choi, Jiun-Sheng Chen, Ruiying Zhao, Jian Chen, Chris Gully, Colin Carlock, Yuan Qi, Ya Zhang, Yun Wu, Francisco Esteva, Yongde Luo, Wallace L. McKeehan, Joe E. Ensor, Gabriel N. Hortobagyi, Lajos Pusztai Pusztai, W. Fraser Symmans, Mong-Hong Lee, Sai-Ching J. Yeung. Obesity induces changes in adipokines profile and activates Akt/mTOR signaling accelerating breast carcinogenesis and tumor growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3927. doi:10.1158/1538-7445.AM2014-3927