Obesity is an established risk factor for basal-like breast cancer (BBC), an aggressive triple negative subtype that disproportionately affects young African American women. How obesity promotes BBC remains unknown, motivating provocative question A2: How does obesity contribute to cancer risk? The goal of this proposal is address this provocative question by utilizing mouse models of BBC to identify molecular mechanisms by which obesity promotes BBC. Furthermore, this project will evaluate whether the pro-tumorigenic effects of obesity are reversible and will establish the role of the hepatocyte growth factor (HGF) signaling cascade in this process. This project builds on our previous data demonstrating that high fat diet-induced obesity decreases tumor latency in a genetically engineered mouse model (GEMM) of BBC, concomitant with alterations in HGF secretion and cMET receptor expression. Our hypothesis is that obesity-induced effects on breast carcinogenesis can be reversed through dietary intervention and/or pharmacologic means via a mechanism that depends upon HGF/cMET signaling.
We aim to link epidemiologic observations linking obesity and BBC with mechanistic underpinnings and to identify viable strategies for reducing obesity-associated breast cancer by studying the role of HGF/cMET signaling in obesity-associated BBC latency and progression.
In Aim 1, we will evaluate whether these expression changes are reversible with dietary modification (cross over to a low fat diet after high fat diet-induced obesity onset) and we will quantify how caloric restriction affects the normal mammary gland and tumor latency.
In Aim 2, we will pharmacologically target the HGF/cMET pathway in high fat diet-induced obese animals to evaluate the effect on latency.
Both aims will take advantage of established model systems and will use gene and protein expression analysis of normal breast tissue to monitor the molecular effects of obesity, diet, and HGF signaling in the microenvironment from which BBC tumors arise. If these studies are successful, this research will establish whether HGF/Met oncogenic signaling plays a role in BBC etiology, leading to new avenues of research on genetic susceptibility to obesity-associated risk. Targeted intervention through dietary interventions or pharmacologic therapies would transform the field of obesity-associated cancer prevention and could prevent thousands of breast cancer each year.
Obesity is a contributing factor in at least half of basal-like breast cancers, suggesting that this aggressive subtype of breast cancer may be preventable. Given that basal-like breast cancer is most prevalent in young African American women, targeted prevention may help reduce mortality disparities. This project tests the reversibility of obesity-associated risk using dietary and pharmacologic interventions, leading to identification of mechanistically-based strategies for prevention of obesity-associated BBC.
|Cozzo, Alyssa J; Sundaram, Sneha; Zattra, Ottavia et al. (2016) cMET inhibitor crizotinib impairs angiogenesis and reduces tumor burden in the C3(1)-Tag model of basal-like breast cancer. Springerplus 5:348|
|Johnson, Amy R; Makowski, Liza (2015) Nutrition and metabolic correlates of obesity and inflammation: clinical considerations. J Nutr 145:1131S-1136S|
|Sundaram, Sneha; Freemerman, Alex J; Galanko, Joseph A et al. (2014) Obesity-mediated regulation of HGF/c-Met is associated with reduced basal-like breast cancer latency in parous mice. PLoS One 9:e111394|