Abstract 2645: Obesity promotes tumor growth, reduces breast tumor latency and correlates with neovascularization: Therapeutic and diagnostic implications
Authors: Roy Roopali , Yang Jiang , Merritt Lauren , Alluine Justine , Chodosh Lewis A. , Moses Marsha A. 
Published: September 2020

Abstract
Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). The goal of this study was to determine whether diet-induced obesity (DIO) promotes (i) shorter tumor latency, (ii) escape from tumor dormancy, and (iii) acceleration of tumor growth, angiogenesis and metastasis and to elucidate the underlying mechanism/s. Two different BC models, an orthotopic model (luciferase/MDA-MB-436 injected into the mammary fat pad (MFP) of SCID mice) and a transgenic model (doxycycline-driven conditional MMTV/TWNT/luciferase) were utilized. To model the effect of obesity on PM BC, mice were ovariectomized (OVX) before being placed on a DIO (obese) or normal chow (NC; lean) regimen. In both the orthotopic and transgenic BC models, obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared to lean mice. Breast tumors in OVX/DIO mice had significantly higher microvessel density (MVD), SMA+ mature vessels and increased aggressive local invasion into the surrounding fat pad and muscle. OVX/DIO TWNT mice displayed a significantly shorter tumor latency period (7 vs. &gt;24 wk, P=0.003) compared to OVX/NC mice. Levels of VEGF, IL-6, bFGF, Lcn-2 and MMP-9 were higher, whereas Tsp-1 levels were lower, in the sera/urine of DIO mice during tumor progression, suggesting that these circulating factors could serve as surrogate biomarkers of BC development. OVX/DIO tumors had increased expression of the angiogenic factors VEGF and bFGF and higher pVEGFR2. Systematic time-course analysis of MFP in the TWNT BC model indicated that DIO MFP achieved advanced tumor proliferative and angiogenic status at significantly earlier time points compared to NC MFP. DIO MFP also exhibited an increased incidence of extensive hyperplasia and carcinoma in situ at earlier time points, suggesting that obesity promotes tumor initiation as well as progression. Hyperplastic ducts and microscopic neoplastic lesions (≤1mm) in DIO MFP in the early phases of tumor development displayed increased Ki67 staining and were associated with significantly higher numbers of blood vessels. Collectively, our data suggest that PM obesity reduces breast tumor latency, promotes escape from tumor dormancy and initiates aggressive tumor growth via increased angiogenesis. Consistent with these findings, targeting angiogenesis via a small molecule inhibitor resulted in delayed tumor formation compared to vehicle-treated mice in the OVX/DIO TWNT BC model, suggesting that targeting angiogenesis may be a useful strategy in obesity-driven breast tumor initiation and progression. Ongoing studies in our laboratory are investigating the mechanism(s) by which an obesogenic microenvironment mediates these effects. [This work was supported by NIH RO1CA185530, the Karp Family Foundation and the Breast Cancer Research Foundation]
Citation Format: Roopali Roy, Jiang Yang, Lauren Merritt, Justine Alluine, Lewis A. Chodosh, Marsha A. Moses. Obesity promotes tumor growth, reduces breast tumor latency and correlates with neovascularization: Therapeutic and diagnostic implications [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2645.