Loss of β4 integrin subunit reduces the tumorigenicity of MCF7 mammary cells and causes apoptosis upon hormone deprivation

Purpose: The alpha(6)beta(4) integrin, a laminin receptor, has been implicated from many studies in tumor progression and invasion. We showed that the 134 integrin subunit associates with the ErbB-2 tyrosine kinase in human mammary carcinoma cell lines and that its overexpression in NlH3T3/ ErbB-2- transformed cells causes a constitutive activation of phosphatidylinositol 3-kinase (PI3K), inducing a strong increase of their invasive capacity, In this study, we investigated the biological consequences of interference with the endogenous beta(4) integrin subunit expression. Experimental Design: In vitro and in vivo tumor growth and the biochemical consequences Of N integrin inactivation were studied in mammary tumor cells by using short hairpin RNA approach. Results: Our data show that tumor growth of mammary tumor cells strictly depends on beta(4) expression, confirming the relevance of beta(4) protein in these cells. Moreover, interference with N expression significantly reduces endogenous PI3K activity and AKT and mammalian target of rapamycin phosphorylation. Accordingly, with these results and considering that PI3K activity in mammary tumor plays a relevant role in hormone resistance, we asked whether beta(4) expression might be relevant for hormone responsiveness in these cells. Data reported indicate that the interference with endogenous beta(4) expression, upon hormone deprivation, induces caspase-9 and cytochrome c - mediated apoptosis, which is enhanced upon tamoxifen treatment. On the other hand, the expression of myr-AKT in MCF7 beta(4)- short hairpin RNA cells rescues the cells from apoptosis in the absence of hormones and upon tamoxifen treatment. Conclusions: Overall, these results confirm the relevance of beta(4) expression in mammary tumors and indicate this integrin as a relevant target for tumor therapy.