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Loss of ß₄ Integrin Subunit Reduces the Tumorigenicity of MCF7 Mammary Cells and Causes Apoptosis upon Hormone Deprivation

Authors' Affiliations: ¹ Molecular Oncogenesis Laboratory, Department of Experimental Oncology, Regina Elena Cancer Institute, Rome, Italy and ² Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy

Requests for reprints: Rita Falcioni, Regina Elena Cancer Institute, Department of Experimental Oncology, Molecular Oncogenesis Laboratory, Via delle Messi d'Oro, 156, 00158 Rome, Italy. Phone: 39-06-52662535; Fax: 39-06-52662505; E-mail: falcioni{at}ifo.it.

Purpose: The ₆ß₄ integrin, a laminin receptor, has been implicated from many studies in tumor progression and invasion. We showed that the ß₄ integrin subunit associates with the ErbB-2 tyrosine kinase in human mammary carcinoma cell lines and that its overexpression in NIH3T3/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 ß₄ integrin subunit expression.

Experimental Design: In vitro and in vivo tumor growth and the biochemical consequences of ß₄ 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 ß₄ expression, confirming the relevance of ß₄ protein in these cells. Moreover, interference with ß₄ 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 ß₄ expression might be relevant for hormone responsiveness in these cells. Data reported indicate that the interference with endogenous ß₄ 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 ß₄–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 ß₄ expression in mammary tumors and indicate this integrin as a relevant target for tumor therapy.

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