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The 6ß4 Integrin Maintains the Survival of Human Breast Carcinoma Cells In vivo

Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Requests for reprints: Arthur M. Mercurio, Department of Cancer Biology, University of Massachusetts Medical School, LRB-408, 364 Plantation Street, Worcester, MA 01605. Phone: 508-856-8676; Fax: 508-856-1310; E-mail: arthur.mercurio{at}umassmed.edu.

The 6ß4 integrin has been widely implicated in carcinoma function in vitro; however, in vivo data are scarce. To determine the importance of 6ß4 in tumor progression, a SUM-159 breast carcinoma cell line that is essentially devoid of 6ß4 expression was generated using an RNA interference strategy. Loss of 6ß4 expression inhibits colony formation in soft agar assays, suggesting a vital role for 6ß4 in survival signaling and anchorage-independent growth. Orthotopic injection of the ß4-deficient cell line into the mammary fat pad of immunocompromised mice yielded significantly fewer and smaller tumors than the control cell line, revealing a role for the 6ß4 integrin in tumor formation. Under conditions that mimicked the in vivo environment, decreased expression of the 6ß4 integrin led to enhanced apoptosis as determined by the percentage of Annexin V-FITC+, PI– cells and the presence of caspase-3 cleavage products. Recombinant vascular endothelial growth factor (VEGF) significantly inhibited the cell death observed in the ß4-deficient cell line, demonstrating the importance of VEGF expression in this survival pathway. Furthermore, loss of 6ß4 expression leads to enhanced apoptosis and reduced expression of VEGF in breast carcinoma cells in vivo. Importantly, the specificity of 6ß4 in both the in vitro and in vivo assays showed that reexpression of the ß4 subunit into the ß4-deficient cell line could rescue the functional phenotype. Taken together, these data implicate the 6ß4 integrin in tumor formation by regulating tumor cell survival in a VEGF-dependent manner.

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