Abstract
IntroductionActivation of focal adhesion kinase (FAK) is hypothesized to play an important role in the pathogenesis of human breast cancer.MethodsTo 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.ResultsAlthough 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.ConclusionsWhile 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.
Highlights
Activation of focal adhesion kinase (FAK) is hypothesized to play an important role in the pathogenesis of human breast cancer
Given the dramatic impact of FAK deletion on polyomavirus middle T (PyVmT) tumour induction, we evaluated whether deletion of FAK in an activated human epithelial growth factor receptor (ErbB2) mouse model resulted in a comparable phenotype
Mammary tumours that arise in conditional FAK mice selectively retain FAK due to loss of Cre expression To evaluate the role of FAK in ErbB2 mammary tumour progression, we interbred mice carrying conditional FAK alleles to separate transgenic strains carrying either mammary tumour virus (MMTV)-Cre [18] or MMTV-activated ErbB2 (NDL 2-5) [20]
Summary
Activation of focal adhesion kinase (FAK) is hypothesized to play an important role in the pathogenesis of human breast cancer. Elevated expression of FAK has been associated with highly invasive human breast cancers [1,2]. Activation of FAK has been observed in human breast cancer cell lines expressing elevated. Because germline deletion of FAK results in embryonic lethality [10,11], it is difficult to assess whether complete ablation of FAK could impact on chemical skin carcinogenesis. To circumvent this limitation, the same group demonstrated that conditional ablation of FAK in the skin resulted in an absolute block in the progression of benign papilloma lesions to malignant carcinomas in this model [12]. It has been shown that prostate-specific ablation of FAK in an SV40 T antigen mouse model resulted in the inability of prostate tumours to progress to the aggressive neuroendocrine phenotype [13]
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