All ETDs from UAB

Advisory Committee Chair

Rosa A Serra

Advisory Committee Members

Chengbei Chang

Andra R Frost

Michael A Miller

Danny R Welch

Document Type

Dissertation

Date of Award

2008

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

cancer is the second most common cancer worldwide behind lung cancer, affecting women of all ages, races, ethnicities, and socioeconomic strata. Concerted efforts have been made to understand this heterogeneous disease from the clinical stage down to the molecular level. Importantly, it has become clear that an understanding of the normal biology of the breast at all stages of development is needed to gain insight into how alterations in normal regulatory networks contribute to the initiation and development of breast cancer. TGF-ß plays a role in growth and patterning of the mammary gland and alterations in its signaling exhibit biphasic effects during tumorigenesis. Here, we identified Wnt5a as a downstream effector of TGF-ß within the mammary gland. Furthermore, we established a requirement of Wnt5a for 1) orchestrating proper mammary gland development at multiple stages and 2) TGF-ß-mediated inhibition of ductal growth. We went on to establish that TGF-ß and Wnt5a act to inhibit the canonical Wnt/ß-catenin pathway in the mammary gland, having implications on development, stem cell dynamics, and tumorigenesis. Together, this dissertation provides a novel link between TGF-ß and Wnt pathways that might extend beyond the mammary gland.

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