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The α6β4 Integrin Maintains the Survival of Human Breast Carcinoma Cells In vivo

2005; American Association for Cancer Research; Volume: 65; Issue: 23 Linguagem: Inglês

10.1158/0008-5472.can-05-2327

1538-7445

Elizabeth A. Lipscomb, Kaylene J. Simpson, Stephen Lyle, Jennifer E. Ring, Aisling S. Dugan, Arthur M. Mercurio,

Chemokine receptors and signaling

Abstract The α6β4 integrin has been widely implicated in carcinoma function in vitro; however, in vivo data are scarce. To determine the importance of α6β4 in tumor progression, a SUM-159 breast carcinoma cell line that is essentially devoid of α6β4 expression was generated using an RNA interference strategy. Loss of α6β4 expression inhibits colony formation in soft agar assays, suggesting a vital role for α6β4 in survival signaling and anchorage-independent growth. Orthotopic injection of the β4-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 α6β4 integrin in tumor formation. Under conditions that mimicked the in vivo environment, decreased expression of the α6β4 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 β4-deficient cell line, demonstrating the importance of VEGF expression in this survival pathway. Furthermore, loss of α6β4 expression leads to enhanced apoptosis and reduced expression of VEGF in breast carcinoma cells in vivo. Importantly, the specificity of α6β4 in both the in vitro and in vivo assays showed that reexpression of the β4 subunit into the β4-deficient cell line could rescue the functional phenotype. Taken together, these data implicate the α6β4 integrin in tumor formation by regulating tumor cell survival in a VEGF-dependent manner.