Physical and functional interactions between Cas and c-Src induce tamoxifen resistance of breast cancer cells through pathways involving epidermal growth factor receptor and signal transducer and activator of transcription 5b.
High expression of the adaptor molecule Cas has been linked to resistance to the antiestrogen tamoxifen, both in tissue culture and in human tumors. The aim of this study was to elucidate the mechanism(s) by which overexpression of Cas confers resistance to tamoxifen. Cas overexpression in MCF-7 breast cancer cells was shown to alleviate both tamoxifen-mediated growth inhibition and induction of apoptosis. This enhancement of cell proliferation/survival occurred in the absence of detectable effects on estrogen receptor (ER) transcriptional activity under conditions where tamoxifen was present, indicating that Cas-dependent tamoxifen resistance is not the result of a switch to an ER-negative phenotype or enhanced responses to the partial agonist activity of tamoxifen. Instead, we present evidence, suggesting that Cas promotes tamoxifen resistance by deregulation of alternative cell proliferation pathways, particularly those mediated through enhanced c-Src protein tyrosine kinase activity arising from Cas/c-Src interactions. Overexpression of Cas was found to drive endogenous c-Src into complex with Cas, a process that has been shown previously to cause up-regulation of c-Src tyrosine kinase activity. MCF-7 cells overexpressing Cas exhibited increased phosphorylation of two c-Src substrates, Tyr845 in the kinase domain of the epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription (STAT) 5b. Importantly, Cas-dependent protection from the antiproliferative effects of tamoxifen was reversed by the expression of dominant inhibitory variants of these substrates (Y845F EGFR and COOH-terminally truncated STAT5b). Based on these findings, we suggest that the Cas/c-Src/EGFR/STAT5 signaling axis is a major regulator of tamoxifen-resistant breast cancer cell growth and survival.
Riggins
Rebecca B
RB
Department of Microbiology and Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Thomas
Keena S
KS
Ta
Huy Q
HQ
Wen
Jie
J
Davis
Rebecca J
RJ
Schuh
Natasha R
NR
Donelan
Stacey S
SS
Owen
Katherine A
KA
Gibson
Matthew A
MA
Shupnik
Margaret A
MA
Silva
Corinne M
CM
Parsons
Sarah J
SJ
Clarke
Robert
R
Bouton
Amy H
AH
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019556:COS Cells; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*; D019061:src-Family Kinases
D050719:Crk-Associated Substrate Protein; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D013629:Tamoxifen; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human