Effects of the Breast Tissue Microenvironment on the Progression of Breast Cancer

Breast cancer is the second most common cancer in women. The breast tumor will remodel its surrounding environment to make it more permissive to invasion and eventual metastasis through alterations of the extracellular matrix (ECM), cells, and secretions. Examining these changes proves important as they give possible targets for therapeutics. There are multiple different risk factors for breast cancer and they all can cause changes in the normal breast environment. These changes in the normal breast microenvironment are critical to investigate as they can allow for the progression of breast cancer. In this dissertation, first we examined the normal breast structure of mice groups with different generations of obesity. These matrices showed differences in the collagen structure, namely collagen curvature, that breast cells responded with increased migration and invasion when seeded on the ECM from mice with a high-fat dam. We then investigated if an increase in leptin concentration caused alterations in collagen curvature. Next, we investigated 3D tumor models and created a 3D bioprinted human obesity breast tumor model. After being characterized, both 2D breast cancer cell culture and our 3D tumor spheroid model were treated with different extracellular vesicle (EV) groups where we saw an increase in cell migration and invasion for those constructs treated with EVs from fibroblasts closer to the tumor. Finally, we examined the impact of chemotherapeutics on normal breast fibroblast ECM production. Those fibroblasts treated with doxorubicin had increased reactive oxygen species production and the ECM they generated had a curvier collagen structure, which caused breast cancer cells to have increased migration and invasion when seeded onto the generated ECM. Overall, through these studies we were able to show how different changes in collagen structure or proximity to a tumor can affect the progression of breast cancer cells to be more motile and invasive.