Abstract PR04: Tissue tension promotes mammary stemness and breast cancer aggression

Breast cancers frequently develop treatment resistance that leads to recurrence, dissemination and patient mortality. Among the mechanisms that foster treatment resistance is the ability of tumor cells to undergo an epithelial-to-mesenchymal transition (EMT) and exhibit stem-like behavior. Accumulating evidence now supports the concept that the mechanical properties of the extracellular matrix microenvironment can critically influence developmental cell fate and modify several features of tumor progression. Data from our laboratory using preclinical models and clinical samples suggest that tissue tension and elevated mechanosignaling increase prior to and accompany malignant transformation. Therefore, we hypothesize that enhanced tissue mechanical tension and high mechanosignaling foster mammary stemness, EMT and breast cancer aggression. We tested this prediction by generating transgenic mice conditionally expressing a β1-Integrin clustering mutant (V737N) in the mammary epithelium. V737N expression stimulated integrin-mediated mechanosignaling in mammary epithelial cells (MECs), as determined by elevated phosphorylation of FAK and p130Cas, and this heightened mechanosignaling promoted precocious epithelial ductal branching, end bud formation and increased MEC proliferation in the mammary gland. These mammary phenotypes were accompanied by an increase in the ratio of basal/myoepithelial to luminal MECs in V737N mammary glands. Isolated V737N-expressing MECs possessed hi...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Differentiation Hierarchy and Cancer: Oral Presentations - Proffered Abstracts Source Type: research