Regulation of Breast Carcinoma Progression by the Alpha-6 Integrins

Abstract : During this career development award, I have made significant progress in determining the contribution of the alpha 6 beta 1 integrin receptors to breast cancer. We had previously established that the alpha 6 beta 1 receptor contributes to the growth and survival of breast carcinoma metastases. In addition, we had demonstrated that de novo expression of the integrin beta 4 subunit in breast carcinoma cell lines that lack this integrin subunit increases their invasive potential. During this award period, my work has resulted in an increased understanding of alpha 6 beta 1-dependent breast carcinoma survival and the important role of PI3K and Akt in this function. I have demonstrated that the ability of the alpha 6 beta 4 integrin to promote invasion is related to its activation of phosphoinositide 3-OH kinase (PI3K) and the downstream effectors Rac and PKC epsilon. I identified IRS-1 and IRS-2 as intermediates in the alpha 6 beta 4-dependent activation of PI3K and demonstrated that Y1494 in the beta 4 subunit is essential for this signaling pathway. Finally, I have established an involvement of the src family in alpha 6 beta 4-dependent breast carcinoma invasion. Importantly, this career development award has contributed to my promotion to Assistant Professor, my recruitment to the BIDMC Pathology Department, and my obtaining an NIH-R01 Award that is focused on breast cancer.