title: Brk/PTK6 cooperates with HER2 and Src in regulating breast cancer cell survival and epithelial-to-mesenchymal transition.
abstract: Breast tumor kinase (Brk)/protein tyrosine kinase-6 (PTK-6) is a nonreceptor PTK commonly expressed at high levels in breast cancer. Brk interacts closely with members of the human epidermal growth factor receptor (HER) family in breast cancer but the functional role of this interaction remains to be determined. Here, we provide novel mechanistic insights into the role of Brk in regulating cell survival and epithelial-to-mesenchymal transition (EMT) in the context of HER2-positive breast cancer cells. Overexpression of HER2 in MCF7 breast cancer cells (MCF7HER2) led to a higher level of Brk protein and concomitantly reduced Src Y416-phosphorylation, and the cells became mesenchymal in morphology. An in vivo selection of MCF7HER2 cells in nude mice resulted in a subline, termed EMT1, that exhibited not only mesenchymal morphology but also enhanced migration potential. Compared with MCF7HER2 cells, EMT1 cells maintained a similar level of HER2 protein but had much higher level of activated HER2, and the increase in Brk protein and the decrease in Src Y416-phosphorylation were less in EMT1 cells. EMT1 cells exhibited increased sensitivity to both pharmacological inhibition of HER2 and knockdown of Brk than did MCF7HER2 cells. Knockdown of Brk induced apoptosis and partially reversed the EMT phenotype in EMT1 cells. Overexpression of a constitutively active STAT3, a known substrate of Brk, overcame Brk knockdown-induced effects in EMT1 cells. Together, our findings support a new paradigm wherein Brk plays both a complementary and a counterbalancing role in cooperating with HER2 and Src to regulate breast cancer cell survival and EMT.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
authors.forename: Midan
authors.initials: M
authors.lastname: Ai
authors.forename: Ke
authors.initials: K
authors.lastname: Liang
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Songbo
authors.initials: S
authors.lastname: Qiu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D009363:Neoplasm Proteins; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; C088375:PTK6 protein, human
keywords: Brk; EMT; HER2; STAT3; Src; breast cancer; survival