The overwhelming majority of breast cancers originate from the cells that make up the complex network of branching ducts of the mammary gland. Normal development of complex tissue architecture is regulated by a class of proteins known as morphogens, and aberrant morphogenic signaling gives rise to cancer in a number of systems. Epimorphin was recently identified as an essential morphogen in the mammary gland. Although it is known that epimorphin is required for proper development of the mammary gland, its mode of action and possible roles in the abnormal architectural changes that occur in cancer are not understood. There is some evidence that epimorphin might exert its effects on tissue architecture by affecting processes requiring changes in the supportive architecture of the cell, the cytoskeleton. It is my hypothesis that epimorphin directs normal mammary epithelial (tissue) morphogenesis by differentially altering cytoskeletal networks in individual cells and that this process is disrupted in transformed mammary cells. The purpose of this proposal is to delineate the involvement of the cytoskeleton in epimorphin-induced differentiation and to determine how this signaling differs between normal mammary cells and breast cancer cells. Understanding how morphogenic signaling is subverted in breast cancer may give us new insights into cancer development and potential new targets for therapeutic treatments.

The three specific aims described in this proposal represent complementary approaches to investigate the mechanism of epimorphin-induced morphogenesis. They are united by their use of a well-defined epimorphin-mammary epithelial cell culture model to compare normal and cancer cells. Specific Aim 1 focuses on the mechanism of sensing of morphogenic cues and will determine whether isolated cells can process signals for multicellular morphogenesis. This aim is important because cancer cells frequently act in isolation of the rest of their surrounding tissue. Specific Aim 2 focuses on mechanism of signaling and will determine whether epimorphin mediates its effects on morphogenesis by signaling through cytoskeletal regulators. Specific Aim 3 focuses on mechanism of cellular rearrangement and will determine whether epimorphin mediates its effects by altering processes that require rearrangement of the cytoskeleton.

I believe that these studies have the potential to unlock general principles underlying the process of morphogenesis in the mammary gland and will increase our understanding of what goes awry in breast cancer.