University Of Oklahoma Oklahoma City, Oklahoma, United States
Introduction: Breast cancer is the most prevalent invasive cancer in women. Obesity is a key risk factor implicated in the progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Importantly, while breast cancer is often diagnosed as DCIS, it is unknown which lesions will progress to potentially lethal IDC, especially in obesity. The lack of relevant in vitro models hinders a mechanistic understanding of obesity's impact on early disease stages when cancer cells invade the local environment. In a retrospective study on human breast specimens, we analyzed gene expression in DCIS and IDC from women with varying BMI. IDC from women with low BMI resembled DCIS from women with high BMI, suggesting tumor-intrinsic effects of obesity on cancer stage. Gene expression profiles highlighted extracellular matrix (ECM) remodeling and epithelial-to-mesenchymal transition pathways in obesity associated DCIS compared to other specimens. We hypothesize that obesity-induced ECM alterations are critical in promoting DCIS progression.
Materials and
Methods: To test this, we developed a novel 3D in vitro model by isolating and denaturing ECM from lean and obese mouse mammary environments. Human breast cancer cells were cultured in this ECM, and spheroid size and growth rates were analyzed. We performed untargeted mass spectrometry to define the matrix proteome and pathway analysis of enriched networks in lean and obese conditions. Immunoblot assessed cellular changes in cancer associated signaling molecules. Additionally, we employed immunofluorescence to assess changes in YAP signaling pathways in the seeded breast cancer cells.
Results, Conclusions, and Discussions: Preliminary findings showed significantly greater breast cancer sphere size in obese ECM after three days, indicating an obesity-driven ECM shift that fosters proliferation. Cancer cells in obese, but not lean ECM displayed morphological features of invasion and increased nuclear localization of YAP. Our study highlights a crucial role for obesity-induced ECM remodeling in DCIS to IDC transition and in the growth of aggressive breast cancer cells, suggesting therapeutic potential for targeting ECM in obese breast cancer patients with obesity.
Acknowledgements (Optional): Stevi Johnson-Murguia, Queen M. Pierre, Michael Kinter, Rebecca L. Scalzo, Bethany N. Hannafon, and Elizabeth A. Wellberg
