title: Requirement for focal adhesion kinase in the early phase of mammary adenocarcinoma lung metastasis formation.
abstract: An increased expression of focal adhesion kinase (FAK) in a variety of cancers is associated with a poor disease prognosis. To study the role of FAK in breast tumor growth and metastasis formation, we used conditional doxycycline-regulated expression of a dominant-negative acting splice variant of FAK, FAK-related non-kinase (FRNK), in MTLn3 mammary adenocarcinoma cells in a syngeneic Fischer 344 rat tumor and metastasis model. In cell culture, doxycycline-mediated expression of FRNK inhibited MTLn3 cell spreading and migration in association with reduced formation of focal adhesions and phosphorylation of FAK on Tyr(397), but FRNK did not cause apoptosis. Continuous expression of FRNK decreased the primary tumor growth in the mammary fat pad by 60%, which was not due to induction of apoptosis. Lung metastasis formation was almost completely prevented when FRNK was already expressed 1 day before tumor cell injection, whereas expression of FRNK 11 days after injection did not affect lung metastasis formation. FRNK expression during the first 5 days was sufficient to block metastasis formation, excluding the possibility of FRNK-induced dormancy of tumor cells. Together, these data fit with a model wherein FAK is required for breast tumor cell invasion/migration processes that take place in the early phase of metastasis formation. Our findings suggest that FAK is a good candidate for therapeutic intervention of metastasis formation.
authors.affiliation: Department of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Maroesja J
authors.initials: MJ
authors.lastname: van Nimwegen
authors.forename: Saertje
authors.initials: S
authors.lastname: Verkoeijen
authors.forename: Liesbeth
authors.initials: L
authors.lastname: van Buren
authors.forename: Danny
authors.initials: D
authors.lastname: Burg
authors.forename: Bob
authors.initials: B
authors.lastname: van de Water
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology / Q000556:secondary*; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004318:Doxycycline / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006388:Hemagglutinins / Q000096:biosynthesis / Q000235:genetics; D008175:Lung Neoplasms / Q000201:enzymology* / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology*; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D006388:Hemagglutinins; C113183:FAK-related nonkinase; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496052:Ptk2 protein, rat; D004318:Doxycycline