title: Focal adhesion kinase contributes to proliferative potential of ErbB2 mammary tumour cells but is dispensable for ErbB2 mammary tumour induction in vivo.
abstract: BACKGROUND
  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.
authors.affiliation: Goodman Cancer Centre, McGill University, 1160 Pine Ave, west, Montreal, QC, H3A 1A3, Canada.
authors.forename: Hicham
authors.initials: H
authors.lastname: Lahlou
authors.forename: Virginie
authors.initials: V
authors.lastname: Sanguin-Gendreau
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Frame
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
mesh_terms: D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D017353:Gene Deletion; D019426:Integrases / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D047368:Tumor Burden
chemical_list: D050719:Crk-Associated Substrate Protein; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; D019426:Integrases; D051419:Paxillin; D018719:Erb-b2 Receptor Tyrosine Kinases; C493842:Bcar1 protein, mouse; C496062:Pxn protein, mouse; C524056:Erbb2 protein, mouse; C496051:Ptk2 protein, mouse; C496053:Ptk2b protein, mouse; C045073:Cre recombinase