All ETDs from UAB

Advisory Committee Chair

Rosa Serra

Advisory Committee Members

Andra Frost

Susan Ruppert

Robin Lorenz

Jianbo Wang

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

TGF-beta and the Wnt signaling pathways play key roles in regulating ductal growth and branching morphogenesis in the mammary gland. Disruption to this signaling can cause deregulation of the normal mammary stem cell population and foster an environment favorable for tumorigenesis and recurrence. Recent studies show that TGF-beta up-regulates expression of the non-canonical Wnt, Wnt5a, in the mammary gland and that Wnt5a antagonizes canonical Wnt/beta-catenin signaling in mammary epithelial cells. Canonical Wnt/beta-catenin signaling has been strongly implicated in expanding the mammary stem/progenitor cell pool. Here, we test the hypothesis that Wnt5a suppresses the expansion of the mammary stem and progenitor cell population by antagonism of canonical Wnt signaling. Using mammosphere assays to propagate mammary stem/progenitor cells, we demonstrate that Wnt5a treatment limits the size and number of mammospheres and attenuates the expression of canonical Wnt target genes in wild-type cultures. Furthermore, secondary mammospheres previously treated with Wnt5a demonstrate similar inhibition of mammosphere formation. To investigate the effects of Wnt5a on canonical Wnt signaling in mammary tissue in vivo, we generated transgenic mice expressing both MMTV-Wnt1 and MMTV-Wnt5a. MMTV-Wnt1;MMTV-Wnt5a mice showed decreased basal and progenitor cells in non-tumor tissues as well as decreased tumor formation and a shift in tumor phenotype towards less basal-like characteristics. These results suggest a novel mechanism for regulation of mammary stem cells and tumor suppression and warrant future studies to explore the mechanism underlying Wnt5a antagonism of canonical Wnt signaling in greater detail.

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