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5 Contributes to the Tumorigenic Potential of Breast Cancer Cells Through the Src-FAK and MEK-ERK Signaling Pathways

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5 Contributes to the Tumorigenic Potential of Breast Cancer Cells Through the Src-FAK and MEK-ERK Signaling Pathways Oncogene (2013) 32, 3049–3058 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc ORIGINAL ARTICLE Integrin b5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways A Bianchi-Smiraglia, S Paesante and AV Bakin Cancer progression, response to therapy and metastasis depend on tumor microenvironment. Integrins are cell-adhesion receptors that mediate interactions of cells with extracellular matrix. The av-b-family of integrins contributes to tumorigenesis, response to therapy and cancer stem cell biology. Thus, understanding the function of specific integrins in cancer is critical for the development of therapeutic approaches targeting integrins. The study investigated the role of integrin b5 in breast carcinomas by depleting integrin b5 using RNA interference and reexpression of integrin b5. Depletion of integrin b5 in triple-negative breast carcinoma cells markedly reduced tumor take, growth and tumor angiogenesis, whereas reexpression of integrin b5 rescued this phenotype. Reduction in tumor angiogenesis is associated with lower expression of vascular endothelial growth factor-A in integrin b5-depleted tumors. Tumor cells deficient in integrin b5 have lower migration and proliferative capacities. Biochemical assays revealed that integrin b5 mediates the Src-focal adhesion kinase and MEK-extracellular signal-regulated kinase signaling events that operate independently, and inhibition of these pathways phenocopies integrin b5 deficiency. Breast carcinoma cells express high levels of integrin b5, whereas expression of integrin b3 is limited to stromal compartments and integrin b6 is lost in metastatic cells. Together, these findings show a critical role for integrin b5 in the tumorigenic potential of breast carcinoma cells and therapeutic targeting of integrin b5 is especially attractive for triple-negative breast carcinomas, which are refractory to most of the current therapies. Oncogene (2013) 32, 3049–3058; doi:10.1038/onc.2012.320; published online 23 July 2012 Keywords: integrin; focal adhesion kinase (FAK); extracellular signal-regulated kinase (ERK); anchorage-independent growth; transforming growth factor b (TGF-b) INTRODUCTION epithelial–mesenchymal transition and cancer stem cell biology.7,8 The lifetime risk of breast cancer (BC) is currently one in eight Integrin levels are frequently elevated in aggressive tumors, women and advanced BCs are frequently incurable.1 BC is a making these proteins attractive targets for therapy, although heterogeneous disease with several subtypes classified by the function of specific integrins is not fully understood.7 Recent molecular and clinicopathological characteristics.2 Specific studies have shown that integrin b5 contributes to the therapeutic strategies have been developed for treatment of transforming growth factor b (TGF-b)-induced EMT,8 tumor hormone-receptor positive (ER/PR) and HER2-positive subgroups.3 angiogenesis9 and resistance to radio- and chemotherapy.10,11 Breast tumors with low levels of HER2, estrogen and progesterone Integrins lack enzymatic activity and promote intracellular hormone receptors constitute a group of triple-negative BCs signaling by recruiting and activating integrin-associated kinases (TNBCs) that occur more frequently among young women (o50 such as focal adhesion kinase (FAK) and integrin-linked kinase.6,12 years) and in women of African and Hispanic descent.2 This group FAK is a non-receptor tyrosine kinase that is activated at the sites of of BCs does not have a specific targeted therapy because of cell–matrix adhesions and integrin clustering by auto-phosphor- incomplete understanding of the genetic and epigenetic events ylation at Tyr397 and by Src and other tyrosine kinases.13 FAK can causing TNBCs.3 TNBCs account for up to 17% of all breast also mediate signaling of various growth-factor receptors such as carcinomas, and patients with TNBCs present a more aggressive epidermal growth-factor receptor (EGFR), platelet-derived growth- disease and have a shorter survival time compared with other factor receptor, G-protein coupled receptors and hepatocyte subgroups. Significant research effort is directed on identification growth-factor receptor c-MET.12 In particular, the interaction of of therapeutic targets for TNBCs.4,5 Src with FAK at Tyr861 is crucial for integrin b5-mediated signaling BC progression and response to therapy have been linked to in response to vascular endothelial growth-factor (VEGF)14 and Ras tumor-cell interaction with extracellular matrix. Integrins, hetero- transformation of fibroblasts.15 In some systems, FAK can activate dimeric transmembrane matrix receptors, are major mediators of mitogen-activated protein kinases.16–18 Breast tumors with higher cell adhesion to extracellular matrix and extracellular matrix- histological grade and of a triple-negative subtype express induced intracellular signaling.6,7 Several b-integrins of the av-b- elevated levels of FAK.19 Thus, b-integrins and their signaling family, including b1, b3 and b5, have been linked to invasion, components might be potential therapeutic targets in BC. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA. Correspondence: Professor AV Bakin, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm þ Carlton Streets, Buffalo, NY 14263, USA. E-mail: [email protected] Received 7 May 2012; revised 11 June 2012; accepted 15 June 2012; published online 23 July 2012 Integrin b5 in breast cancer A Bianchi-Smiraglia et al 3050 The present work examines the function of integrin b5 in the integrins av, b1 and b5 in normal breast and ductal carcinomas tumorigenic capacity of advanced-stage breast carcinoma cells by (Supplementary Figure 1a). Integrin b6 expression is reduced in modulating integrin b5 levels using RNA interference and forced tumors compared with normal epithelium, similar to tropomyosin-1, expression approaches. The study provides evidence that integrin a known tumor suppressor.22 Integrin b3 is not expressed by b5 facilitates cancer cell migration, anchorage-independent either normal or tumor epithelial tissues. In contrast, the Finak growth and tumor angiogenesis. Integrin b5 enables intracellular data set examining breast stroma21 reveals elevated levels of Src-FAK and MEK-extracellular signal-regulated kinase (ERK) integrin b3 in tumor stroma, whereas integrin b5 is low in this signaling events that operate independently and underlie the compartment (Supplementary Figure 1a). Protein levels of integrins tumorigenic potential of carcinoma cells. Thus, integrin b5isan in BC tissues were assessed using the Human Protein Atlas attractive therapeutic target in aggressive BCs. database (www.proteinatlas.org). This database contains immuno- histochemistry data and the quality-control information for a genome-wide set of targets. High protein levels of av, b1, and b5 RESULTS integrins were found in normal and carcinoma cells, whereas Integrin b5 is expressed in primary and metastatic BC cells integrin b3 staining was limited to stromal cells (Supplementary Previous studies have implicated integrin b5 in pro-tumorigenic Figure 1b), consistent with the Oncomine data. Thus, high levels of activities of TGF-b such as EMT and invasion.8 To address the role integrin b5 are found in breast carcinoma cells, suggesting an of integrin b5 in BC, we measured expression of avb-integrins in important role for this integrin in both TNBC and ER/PR-positive cell lines, representing triple-negative and luminal breast cancer. carcinomas. Semi-quantitative reverse transcription PCR assays showed expression of integrins av, b1 and b5 in non-tumor and cancer cell lines, whereas integrin b6 is markedly reduced in all Integrin b5 is important for the anchorage-independent growth of cancer cells. Integrin b3 expression is low in triple-negative and breast carcinoma cells absent in ER/PR-positive cell lines. Integrins b5, b3 and av were The role of integrin b5 in BC cells was examined by depleting induced by TGF-b1 in triple-negative cell lines: MCF10A, MDA-MB- integrin b5 using RNA interference and testing cell growth in 231 and BT549 (Figure 1a). All the tested cell lines expressed anchorage-independent assays that closely predict the tumori- integrin b5 protein with the highest level in the primary carcinoma genic capacity.23 Protein levels of integrin b5 were effectively Hs578T cells, while integrin b1 is preferentially expressed by triple- reduced in two cell lines representing triple-negative (MDA-MB- negative cells (Figure 1b). These results were validated by the 231) and ER/PR-positive (MCF7) breast carcinomas (Figures 1c and metadata analysis of the Oncomine database (www.oncomi- d). The specificity of small interfering RNA (siRNA) duplexes was ne.org). To distinguish epithelial and stromal compartments of validated in previous studies.8 Depletion of integrin b5 resulted in breast tumors, we assessed two data sets, utilizing a laser 30–40% reduction of soft-agar colonies by both cell lines (Figures microdissection approach for RNA isolation.20,21 The Richardson 1c and d), indicating a critical role of integrin b5 in the Breast2 data set of breast epithelium20 shows high mRNA levels of tumorigenic potential of BC cells. Figure 1. Expression of av-b-integrins in breast carcinoma cell lines. (a) Reverse transcription (RT)–PCR of integrins av, b1, b3, b5andb6inapanelof non-tumorigenic mammary epithelial and breast carcinoma cells treated
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