title: The ShcA PTB domain functions as a biological sensor of phosphotyrosine signaling during breast cancer progression.
abstract: ShcA (SHC1) is an adapter protein that possesses an SH2 and a PTB phosphotyrosine-binding motif. ShcA generally uses its PTB domain to engage activated receptor tyrosine kinases (RTK), but there has not been a definitive determination of the role of this domain in tumorigenesis. To address this question, we employed a ShcA mutant (R175Q) that no longer binds phosphotyrosine residues via its PTB domain. Here, we report that transgenic expression of this mutant delays onset of mammary tumors in the MMTV-PyMT mouse model of breast cancer. Paradoxically, we observed a robust increase in the growth and angiogenesis of mammary tumors expressing ShcR175Q, which displayed increased secretion of fibronectin and expression of integrin α5/β1, the principal fibronectin receptor. Sustained integrin engagement activated Src, which in turn phosphorylated proangiogenic RTKs, including platelet-derived growth factor receptor, fibroblast growth factor receptor, and Met, leading to increased VEGF secretion from ShcR175Q-expressing breast cancer cells. We defined a ShcR175Q-dependent gene signature that could stratify breast cancer patients with a high microvessel density. This study offers the first in vivo evidence of a critical role for intracellular signaling pathways downstream of the ShcA PTB domain, which both positively and negatively regulate tumorigenesis during various stages of breast cancer progression.
authors.affiliation: Lady Davis Institute for Medical Research, McGill Centre for Bioinformatics, McGill University, Goodman Cancer Research Centre, Montreal, Quebec, Canada.
authors.forename: Ryuhjin
authors.initials: R
authors.lastname: Ahn
authors.forename: Valerie
authors.initials: V
authors.lastname: Sabourin
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Ha
authors.forename: Sean
authors.initials: S
authors.lastname: Cory
authors.forename: Gordana
authors.initials: G
authors.lastname: Maric
authors.forename: Young Kyuen
authors.initials: YK
authors.lastname: Im
authors.forename: W Rod
authors.initials: WR
authors.lastname: Hardy
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.forename: Michael
authors.initials: M
authors.lastname: Hallett
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Josie
authors.initials: J
authors.lastname: Ursini-Siegel
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D005353:Fibronectins; D039081:Integrin alpha5beta1; D055765:Shc Signaling Adaptor Proteins; D042461:Vascular Endothelial Growth Factor A; D019000:Phosphotyrosine; D020794:Receptor Protein-Tyrosine Kinases