Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Ellen Puré

Abstract

Obesity is a known factor for breast cancer development, and contributes to breast tumorigenesis through multiple mechanisms, not all of which are well understood. In particular, the role of mesenchymal stromal cells and the extracellular matrix (ECM) in mediating obesity’s effect on breast cancer is understudied. Using murine models of diet-induced obesity and breast cancer, we investigated the role of the ECM-modulating protease fibroblast activation protein (FAP) in these diseases. We conclude that FAP can simultaneously restrain weight gain and adipocyte hypertrophy while promoting early breast tumorigenesis. Using cellular models of ECM synthesis, adipogenesis, and tumorigenic behavior, we demonstrate that FAP promotes collagen fibrillogenesis, and that the resultant ECM both restrains lipid accumulation in adipocytes and promotes proliferation of epithelial cells. FAP+/+ cells also demonstrate reduced adipogenic differentiation relative to FAP-/- cells, while promoting the formation of cancer cell spheroids. From these data we conclude that FAP, in part through its role in collagen remodeling, functions at the intersection between obesity and breast cancer.

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