Src kinase promotes adhesion-independent activation of FAK and enhances cellular migration in tamoxifen-resistant breast cancer cells.
Src kinase is intimately involved in the control of matrix adhesion and cell migration through its ability to modulate the activity of focal adhesion kinase (FAK). In light of our previous observations that acquisition of tamoxifen resistance in breast cancer cells is accompanied by elevated Src kinase activity, we wish to investigate whether FAK function is also altered in these cells and if this leads to an enhanced migratory phenotype. In in vitro adhesion assays, tamoxifen-resistant (TamR) MCF7 cells had a greater affinity for the matrix proteins fibronectin, laminin, vitronectin and collagen and subsequently demonstrated a much greater migratory capacity across these substrates compared to their weakly-migratory, endocrine-sensitive counterparts. Additionally, elevated levels of activated Src in TamR cells promoted an increase in FAK phosphorylation at Y861 and Y925 and uncoupled FAK activation from an adhesion-dependent process. Inhibition of Src activity using the Src/Abl inhibitor AZD0530 reduced FAK activity, suppressed cell spreading on matrix-coated surfaces and significantly inhibited cell migration. Our data thus suggest that Src kinase plays a central role in the enhanced migratory phenotype that accompanies endocrine resistance through its modulation of FAK signalling and demonstrates the potential use of Src inhibitors as potent suppressors of tumour cell migration.
Hiscox
Stephen
S
Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3XF, Wales. HiscoxSE1@cf.ac.uk
Jordan
Nicola J
NJ
Morgan
Liam
L
Green
Tim P
TP
Nicholson
Robert I
RI
D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D019008:Drug Resistance, Neoplasm; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D013629:Tamoxifen / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000502:physiology*
D013629:Tamoxifen; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases