The Role of Integrin Signaling in Breast Cancer.

Abstract : During this fellowship award, I made considerable progress in understanding the contribution of the alpha6 integrin receptors to breast carcinoma progression. I developed a dominant negative strategy to knock-out' the expression of the alpha6beta1 integrin in a highly metastatic breast carcinoma cell line (MDA-MB-435). After depletion of alpha6beta1 surface expression, these cells are deficient in their growth in the mammary fat pad of athymic mice and can no longer survive as metastases in the lungs and liver. These findings suggest that the alpha6beta1 integrin plays an important role in regulating the growth and survival of breast carcinoma. I also established MDA-MB-435 transfectants that express the alpha6beta4 integrin receptor. These cells have a marked increase in their ability to invade through basement membrane matrices in vitro. I determined that the mechanism by which this integrin promotes invasion involves a preferential and localized targeting of phosphoinositide-3 OH kinase (PI 3-K) activity. The small GTP-binding protein Rac is downstream of PI 3-K in the cells examined and it is involved in invasion. Collectively, these findings provide a mechanism for the involvement of alpha6beta4 in promoting carcinoma invasion and invoke a novel function for PI 3-K signaling.