The Role of Src in Mammary Epithelial Tumorigenesis
Annual summary rept. 15 Apr 2005-14 Apr 2006
CALIFORNIA UNIV BERKELEY
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Src kinases represent a family of non-receptor tyrosine kinases that mediate a number of signaling pathways and cell processes that become deregulated during the tumorigenic process such as cell proliferation, growth, motility, and survival. Since its discovery about 35 years ago as the first known oncogene, the scientific literature has focused on the mutant, oncogenic form of c-Src v-Src and its effects in the transformation of fibroblast cells. While these studies have gained insight into several aspects of Src signaling and biology, the role of endogenous c-Src in mammary epithelial cells remains unclear. This proposal aims to use various mammary carcinoma cell lines to examine the role of endogenous Src in two aspects of breast cancer biology, namely, the early event of the loss of proper cell polarity and acini architecture and the later event of increased migration and invasion capabilities. In addition, the proposal will examine the role of Src in more physiologically relevant three-dimensional cultures by employing the commercially available Matrigel which contains components of extracellular matrix proteins to supply mammary tumor cells with proper polarity cues. Using Src-specific pharmacological inhibitors, our laboratory has found that T4-2 cells polarized and formed acinus-like structures in 3-D cultures accompanied by a concomitant downregulation of AKT and ERK phosphorylation. Inhibition of Src in the more invasive MDA-MB-231 mammary carcinoma cells prevents the formation of invadopodia in 3-D cultures. Using the dominant-negative mutant of Src in MDA-MB- 231 cells, we have confirmed that Src signaling is required for invadopodia formation. Biochemical and cell biological studies will be aimed at delineating the important downstream effectors of Src involved in loss of acini architecture and gain of invasive capabilities of mammary tumor cells.
- Anatomy and Physiology
- Medicine and Medical Research