This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lipscomb, E. A. Articles by Mercurio, A. M. Search for Related Content PubMed PubMed Citation Articles by Lipscomb, E. A. Articles by Mercurio, A. M.

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.

This article has been cited by other articles:

				T. H. Kim, H. I. Kim, Y. H. Soung, L. A. Shaw, and J. Chung Integrin ({alpha}6{beta}4) Signals Through Src to Increase Expression of S100A4, a Metastasis-Promoting Factor: Implications for Cancer Cell Invasion Mol. Cancer Res., October 1, 2009; 7(10): 1605 - 1612. [Abstract] [Full Text] [PDF]

				S. M. K. Pulukuri, J. A. Knost, N. Estes, and J. S. Rao Small Interfering RNA-Directed Knockdown of Uracil DNA Glycosylase Induces Apoptosis and Sensitizes Human Prostate Cancer Cells to Genotoxic Stress Mol. Cancer Res., August 1, 2009; 7(8): 1285 - 1293. [Abstract] [Full Text] [PDF]

				X. Yang, B. Pursell, S. Lu, T.-K. Chang, and A. M. Mercurio Regulation of {beta}4-integrin expression by epigenetic modifications in the mammary gland and during the epithelial-to-mesenchymal transition J. Cell Sci., July 15, 2009; 122(14): 2473 - 2480. [Abstract] [Full Text] [PDF]

				G. Bon, S. E. Di Carlo, V. Folgiero, P. Avetrani, C. Lazzari, G. D'Orazi, M. F. Brizzi, A. Sacchi, S. Soddu, G. Blandino, et al. Negative Regulation of {beta}4 Integrin Transcription by Homeodomain-Interacting Protein Kinase 2 and p53 Impairs Tumor Progression Cancer Res., July 15, 2009; 69(14): 5978 - 5986. [Abstract] [Full Text] [PDF]

				R. Sadej, H. Romanska, G. Baldwin, K. Gkirtzimanaki, V. Novitskaya, A. D. Filer, Z. Krcova, R. Kusinska, J. Ehrmann, C. D. Buckley, et al. CD151 Regulates Tumorigenesis by Modulating the Communication between Tumor Cells and Endothelium Mol. Cancer Res., June 1, 2009; 7(6): 787 - 798. [Abstract] [Full Text] [PDF]

				L. Yang, L. Zhang, Q. Wu, and D. D. Boyd Unbiased Screening for Transcriptional Targets of ZKSCAN3 Identifies Integrin {beta}4 and Vascular Endothelial Growth Factor as Downstream Targets J. Biol. Chem., December 12, 2008; 283(50): 35295 - 35304. [Abstract] [Full Text] [PDF]

				U. Dutta and L. M. Shaw A Key Tyrosine (Y1494) in the {beta}4 Integrin Regulates Multiple Signaling Pathways Important for Tumor Development and Progression Cancer Res., November 1, 2008; 68(21): 8779 - 8787. [Abstract] [Full Text] [PDF]

				S. Lu, K. Simin, A. Khan, and A. M. Mercurio Analysis of Integrin {beta}4 Expression in Human Breast Cancer: Association with Basal-like Tumors and Prognostic Significance Clin. Cancer Res., February 15, 2008; 14(4): 1050 - 1058. [Abstract] [Full Text] [PDF]

				J. C. Friedland, J. N. Lakins, M. G. Kazanietz, J. Chernoff, D. Boettiger, and V. M. Weaver {alpha}6beta4 integrin activates Rac-dependent p21-activated kinase 1 to drive NF-{kappa}B-dependent resistance to apoptosis in 3D mammary acini J. Cell Sci., October 15, 2007; 120(20): 3700 - 3712. [Abstract] [Full Text] [PDF]

				K. D. Merdek, X. Yang, C. A. Taglienti, L. M. Shaw, and A. M. Mercurio Intrinsic Signaling Functions of the beta4 Integrin Intracellular Domain J. Biol. Chem., October 12, 2007; 282(41): 30322 - 30330. [Abstract] [Full Text] [PDF]

				V. Folgiero, R. E. Bachelder, G. Bon, A. Sacchi, R. Falcioni, and A. M. Mercurio The {alpha}6{beta}4 Integrin Can Regulate ErbB-3 Expression: Implications for {alpha}6{beta}4 Signaling and Function Cancer Res., February 15, 2007; 67(4): 1645 - 1652. [Abstract] [Full Text] [PDF]

				A. Bertotti, P. M. Comoglio, and L. Trusolino {beta}4 integrin activates a Shp2-Src signaling pathway that sustains HGF-induced anchorage-independent growth J. Cell Biol., December 18, 2006; 175(6): 993 - 1003. [Abstract] [Full Text] [PDF]

				G. Bon, V. Folgiero, G. Bossi, L. Felicioni, A. Marchetti, A. Sacchi, and R. Falcioni Loss of {beta}4 Integrin Subunit Reduces the Tumorigenicity of MCF7 Mammary Cells and Causes Apoptosis upon Hormone Deprivation. Clin. Cancer Res., June 1, 2006; 12(11): 3280 - 3287. [Abstract] [Full Text] [PDF]

				K. Wilhelmsen, S. H.M. Litjens, and A. Sonnenberg Multiple Functions of the Integrin {alpha}6{beta}4 in Epidermal Homeostasis and Tumorigenesis Mol. Cell. Biol., April 15, 2006; 26(8): 2877 - 2886. [Full Text] [PDF]