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      Focal adhesion kinase contributes to proliferative potential of ErbB2 mammary tumour cells but is dispensable for ErbB2 mammary tumour induction in vivo

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          Abstract

          Introduction

          Activation of focal adhesion kinase (FAK) is hypothesized to play an important role in the pathogenesis of human breast cancer.

          Methods

          To directly evaluate the role of FAK in mammary tumour progression, we have used a conditional FAK mouse model and mouse mammary tumour virus (MMTV)-driven Cre recombinase strain to inactivate FAK in the mammary epithelium of a transgenic mouse model of ErbB2 breast cancer.

          Results

          Although mammary epithelial disruption of FAK in this model resulted in both a delay in onset and a decrease in the number of neoplastic lesions, mammary tumours occurred in 100% of virgin female mice. All of the tumours and derived metastases that developed were proficient for FAK due to the absence of Cre recombinase expression. The hyperplastic epithelia where Cre-mediated recombination of FAK could be detected exhibited a profound proliferative defect. Consistent with these observations, disruption of FAK in established tumour cells resulted in reduced tumour growth that was associated with impaired proliferation. To avoid the selection for FAK-proficient ErbB2 tumour epithelia through escape of Cre-mediated recombination, we next intercrossed the FAK conditional mice with a separate MMTV-driven ErbB2 strain that co-expressed ErbB2 and Cre recombinase on the same transcriptional unit.

          Conclusions

          While a delay in tumour induction was noted, FAK-deficient tumours arose in 100% of female animals indicating that FAK is dispensable for ErbB2 tumour initiation. In addition, the FAK-null ErbB2 tumours retained their metastatic potential. We further demonstrated that the FAK-related Pyk2 kinase is still expressed in these tumours and is associated with its downstream regulator p130Cas. These observations indicate that Pyk2 can functionally substitute for FAK in ErbB2 mammary tumour progression.

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          Most cited references31

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          Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271.

          Cancer cells are characterized by the ability to grow in an anchorage-independent manner. The activity of the nonreceptor tyrosine kinase, focal adhesion kinase (FAK), is thought to contribute to this phenotype. FAK localizes in focal adhesion plaques and has a role as a scaffolding and signaling protein for other adhesion molecules. Recent studies show a strong correlation between increased FAK expression and phosphorylation status and the invasive phenotype of aggressive human tumors. PF-562,271 is a potent, ATP-competitive, reversible inhibitor of FAK and Pyk2 catalytic activity with a IC(50) of 1.5 and 14 nmol/L, respectively. Additionally, PF-562,271 displayed robust inhibition in an inducible cell-based assay measuring phospho-FAK with an IC(50) of 5 nmol/L. PF-562,271 was evaluated against multiple kinases and displays >100x selectivity against a long list of nontarget kinases. PF-562,271 inhibits FAK phosphorylation in vivo in a dose-dependent fashion (calculated EC(50) of 93 ng/mL, total) after p.o. administration to tumor-bearing mice. In vivo inhibition of FAK phosphorylation (>50%) was sustained for >4 hours with a single p.o. dose of 33 mg/kg. Antitumor efficacy and regressions were observed in multiple human s.c. xenograft models. No weight loss, morbidity, or mortality were observed in any in vivo experiment. Tumor growth inhibition was dose and drug exposure dependent. Taken together, these data show that kinase inhibition with an ATP-competitive small molecule inhibitor of FAK decreases the phospho-status in vivo, resulting in robust antitumor activity.
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            Differential regulation of cell motility and invasion by FAK

            Cell migration and invasion are fundamental components of tumor cell metastasis. Increased focal adhesion kinase (FAK) expression and tyrosine phosphorylation are connected with elevated tumorigenesis. Null mutation of FAK results in embryonic lethality, and FAK−/− fibroblasts exhibit cell migration defects in culture. Here we show that viral Src (v-Src) transformation of FAK−/− cells promotes integrin-stimulated motility equal to stable FAK reexpression. However, FAK−/− v-Src cells were not invasive, and FAK reexpression, Tyr-397 phosphorylation, and FAK kinase activity were required for the generation of an invasive cell phenotype. Cell invasion was linked to transient FAK accumulation at lamellipodia, formation of a FAK–Src-p130Cas–Dock180 signaling complex, elevated Rac and c-Jun NH2-terminal kinase activation, and increased matrix metalloproteinase expression and activity. Our studies support a dual role for FAK in promoting cell motility and invasion through the activation of distinct signaling pathways.
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              Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction.

              Despite evidence demonstrating the role of beta1-integrin in the regulation of cancer cell proliferation in vitro, the importance of this cell adhesion receptor during the initiation and progression of epithelial tumors in vivo remains unclear. Here we have used the Cre/LoxP1 recombination system to disrupt beta1-integrin function in the mammary epithelium of a transgenic mouse model of human breast cancer. Using this approach, we show that beta1-integrin expression is critical for the initiation of mammary tumorigenesis in vivo, and for maintaining the proliferative capacity of late-stage tumor cells. These observations provide a direct demonstration that beta1-integrin plays a critical role in both the initiation and maintenance of mammary tumor growth in vivo.
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                Author and article information

                Contributors
                Journal
                Breast Cancer Res
                Breast Cancer Res
                Breast Cancer Research : BCR
                BioMed Central
                1465-5411
                1465-542X
                2012
                28 February 2012
                : 14
                : 1
                : R36
                Affiliations
                [1 ]Goodman Cancer Centre, McGill University, 1160 Pine Ave. west, Montreal, QC, H3A 1A3, Canada
                [2 ]Departments of Biochemistry and Medicine, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada
                [3 ]Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, EH4 2XR, Edinburgh, UK
                Article
                bcr3131
                10.1186/bcr3131
                3496154
                22373082
                e6b0d1c1-041b-43e4-840c-149133b438ad
                Copyright ©2012 Lahlou et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 21 October 2011
                : 9 February 2012
                : 28 February 2012
                Categories
                Research Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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