title: Mammary gland-specific ablation of focal adhesion kinase reduces the incidence of p53-mediated mammary tumour formation.
abstract: BACKGROUND
  Elevated expression of focal adhesion kinase (FAK) occurs in numerous human cancers including colon-, cervix- and breast cancer. Although several studies have implicated FAK in mammary tumour formation induced by ectopic oncogene expression, evidence supporting a role for FAK in spontaneous mammary tumour development caused by loss of tumour suppressor genes such as p53 is lacking. Alterations in the tumour suppressor gene p53 have been implicated in over 50% of human breast cancers. Given that elevated FAK expression highly correlates with p53 mutation status in human breast cancer, we set out to investigate the importance of FAK in p53-mediated spontaneous mammary tumour development.
  
  
  METHODS
  To directly assess the role of FAK, we generated mice with conditional inactivation of FAK and p53. We generated female p53(lox/lox)/FAK(+/+)/WapCre, p53(lox/lox)/FAK(flox/+)/WapCre and p53(lox/lox)/FAK(flox/-)/WapCre mice, and mice with WapCre-mediated conditional expression of p53(R270H), the mouse equivalent of human p53(R273H) hot spot mutation, together with conditional deletion of FAK, P53(R270H/+)/FAK(lox/+)/WapCre and p53(R270H/+)/FAK(flox/-)/WapCre mice. All mice were subjected to one pregnancy to induce WapCre-mediated deletion of p53 or expression of p53 R270H, and Fak genes flanked by two loxP sites, and subsequently followed the development of mammary tumours.
  
  
  RESULTS
  Using this approach, we show that FAK is important for p53-induced mammary tumour development. In addition, mice with the mammary gland-specific conditional expression of p53 point mutation R270H, the mouse equivalent to human R273H, in combination with conditional deletion of Fak showed reduced incidence of p53(R270H)-induced mammary tumours. In both models these effects of FAK were related to reduced proliferation in preneoplastic lesions in the mammary gland ductal structures.
  
  
  CONCLUSIONS
  Mammary gland-specific ablation of FAK hampers p53-regulated spontaneous mammary tumour formation. Focal adhesion kinase deletion reduced proliferative capacity of p53 null and p53(R270H) mammary epithelial cells but did not lead to increased apoptosis in vivo. Our data identify FAK as an important regulator in mammary epithelial cell proliferation in p53-mediated and p53(R270H)-induced mammary tumour development.
authors.affiliation: 1] Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands [2] Division of Molecular Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: M H A M
authors.initials: MH
authors.lastname: van Miltenburg
authors.affiliation: Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: van Nimwegen
authors.affiliation: Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: Tijdens
authors.affiliation: Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Lalai
authors.affiliation: Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska vägen, 171 76 Solna, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Kuiper
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Klarenbeek
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: P C
authors.initials: PC
authors.lastname: Schouten
authors.affiliation: Laboratory of Toxicology, Pathology and Genetics, National Institute for Public Health and the Environment, Antonie van Leeuwenhoeklaan 9, 3721 MA Bilthoven, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: de Vries
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: van de Water
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D002277:Carcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002296:Carcinosarcoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000201:enzymology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D015994:Incidence; D008321:Mammary Glands, Animal / Q000201:enzymology / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse