Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed in vitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.
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. >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.
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.
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