Obesity promotes tumor growth, reduces breast tumor latency and correlates with neovascularization

Obesity is associated with an increased risk and a poor prognosis for both ER+ and ER- breast cancers (BC). To date, however, few studies have focused on the contribution of obesity to BC. In addition, there is a paucity of in vivo models that reliably recapitulate postmenopausal obesity related to BC development and progression. The goal of this study was to determine whether interactions between adipocytes and breast tumor cells promote BC growth and progression and to identify the underlying mechanism(s) responsible. We found that MDA-MB-436 and MCF-7 BC cells, when treated with the conditioned media of adipocytes from obese individuals (Ad-CM), upregulated a number of angiogenic factors including VEGF-A, Ang-1 and bFGF and suppressed the angiogenic inhibitor Tsp-1. Ad-CM stimulated migration and invasion of MDA-MB-436 and MCF-7 (human) and E-Wnt and M-Wnt (mouse) BC cells. Interestingly, the cellular proliferation rate in response to Ad-CM was stimulated only in the ER+ MCF-7 and E-Wnt cells but not in the ER- BC cells, suggesting that Ad-CM may affect proliferation via an ER-dependent mechanism. After pretreatment with Ad-CM, MDA-MB-436, MCF-7 or M-Wnt BC cells exhibited significantly enhanced EC recruitment as well. Utilizing two different breast tumor models, an orthotopic model (ER-: luciferase-labeled MDA-436 cells injected into the mammary fat pad of SCID mice) and a transgenic model (ER+: doxycycline-driven conditional MMTV/TWNT/luciferase expression), we investigated whether postmenopausal obesity reduces breast tumor latency, promotes angiogenesis and accelerates tumor growth. To model the effect of obesity on postmenopausal BC, mice were ovariectomized (OVX) before inducing obesity via a high-fat diet (HFD) regimen. In the ER- BC model, obese mice had significantly higher tumor frequency, higher tumor volume, and significantly lower median survival. In the ER+ tumor model, obese mice displayed significantly higher tumor frequency, a significantly shorter tumor latency period and a significantly lower median survival time. Tumors in OVX/HFD animals had significantly higher microvessel density (MVD) and an increased number of SMA+ mature vessels. A majority of tumors in OVX/HFD mice displayed aggressive local invasion into the surrounding fat pad and muscle. Proangiogenic factors such as IL-6 (Interleukin-6) and Lcn2 (lipocalin 2) were ~2-fold higher in the sera of obese tumor-bearing mice as compared to controls. Our data suggest that postmenopausal obesity reduces breast tumor latency and promotes aggressive tumor growth via increased angiogenesis. Ongoing studies in our laboratory are investigating the mechanism(s) by which an obesogenic microenvironment mediates these effects. *Authors contributed equally. This work was supported by NIH RO1CA185530. Citation Format: Roopali Roy*, Jiang Yang*, Takaya Shimura, Lauren Merritt, Adelle Dagher, Lewis Chodosh, Marsha A. Moses. Obesity promotes tumor growth, reduces breast tumor latency and correlates with neovascularization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5122.