Tamoxifen treatment promotes phosphorylation of the adhesion molecules, p130Cas BCAR1, FAK and Src, via an adhesion-dependent pathway

• Published in: Oncogene Vol. 25; no. 58; pp. 7597 - 7607
• Main Authors: COWELL, L. N, GRAHAM, J. D, BOUTON, A. H, CLARKE, C. L, O'NEILL, G. M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 07.12.2006; Nature Publishing Group
• Subjects: Adhesion; AKT protein; Antiestrogens; Antineoplastic Agents, Hormonal - pharmacology; Biological and medical sciences; Breast cancer; Cell Adhesion Molecules - metabolism; Cell Line, Tumor; Cell migration; Cell physiology; Cell survival; Cell Survival - drug effects; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell viability; Crk-Associated Substrate Protein - metabolism; Estrogen receptors; Estrogens; Focal adhesion kinase; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Fundamental and applied biological sciences. Psychology; Gynecology. Andrology. Obstetrics; Humans; Kinases; Mammary gland diseases; Medical sciences; Medical treatment; Molecular and cellular biology; Phenotypes; Phosphorylation; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins pp60(c-src) - metabolism; Receptors, Estrogen - metabolism; Signal transduction; Signal Transduction - drug effects; src-Family Kinases - metabolism; Tamoxifen; Tamoxifen - pharmacology; Tumors; Antineoplastic agent; Estrogen receptor; Phosphorylation; Treatment resistance; p130Cas/BCAR1; Enzyme; Transferases; Src kinase; Breast cancer; Malignant tumor; adhesion; Carcinogenesis; Tamoxifene; Mammary gland diseases; Molecules; FAK; Treatment; Cell adhesion; Protein-tyrosine kinase; tamoxifen
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209747

Reports that the adhesion-associated molecule p130Cas/BCAR1 promotes resistance to tamoxifen suggested that adhesion-mediated signalling may be altered by tamoxifen treatment. We find that p130Cas/BCAR1 phosphorylation is enhanced in tamoxifen-treated estrogen receptor (ER)-positive MCF-7 breast cancer cells. The effects of estrogen and tamoxifen were assessed independently and in combination, and the results demonstrate that tamoxifen antagonizes estrogen regulation of p130Cas/BCAR1 phosphorylation. Phosphorylation correlates with tamoxifen ER antagonist effects, as phosphorylation effects are replicated by the pure antiestrogen ICI 182, 780. Correspondingly, phosphorylation is not changed in ER-negative cells exposed to tamoxifen. We show that deletion of the p130Cas/BCAR1 substrate domain substantially reduces tamoxifen-induced phosphorylation of p130Cas/BCAR1 and confers enhanced sensitivity to tamoxifen. P130Cas/BCAR1 forms a phosphorylation-dependent signalling complex with focal adhesion kinase (FAK) and Src kinase that promotes adhesion-mediated cell survival. Therefore, we examined the kinetics of p130Cas/BCAR1, Src and FAK phosphorylation over a 14-day time course and find sustained phosphorylation of these molecules after 7 days exposure to tamoxifen. Inhibition of Src kinase is shown to reduce tamoxifen-promoted p130Cas/BCAR1 phosphorylation and reduce cell viability. Stimulation of the Src/FAK/p130Cas/BCAR1 adhesion signalling pathway in tamoxifen-treated MCF-7 cells does not cause increased migration; however, there is Src-dependent phosphorylation of the cell survival molecule Akt. Correspondingly, Akt inhibition reduces cell viability in cells treated with tamoxifen. We propose that prolonged activation of adhesion-dependent signalling may confer a survival advantage in response to additional cellular insults or alternatively, may poise cells to develop a migratory phenotype in response to additional cellular cues.