title: p66ShcA promotes breast cancer plasticity by inducing an epithelial-to-mesenchymal transition.
abstract: Breast cancers are stratified into distinct subtypes, which influence therapeutic responsiveness and patient outcome. Patients with luminal breast cancers are often associated with a better prognosis relative to that with other subtypes. However, subsets of patients with luminal disease remain at increased risk of cancer-related death. A critical process that increases the malignant potential of breast cancers is the epithelial-to-mesenchymal transition (EMT). The p66ShcA adaptor protein stimulates the formation of reactive oxygen species in response to stress stimuli. In this paper, we report a novel role for p66ShcA in inducing an EMT in HER2(+) luminal breast cancers. p66ShcA increases the migratory properties of breast cancer cells and enhances signaling downstream of the Met receptor tyrosine kinase in these tumors. Moreover, Met activation is required for a p66ShcA-induced EMT in luminal breast cancer cells. Finally, elevated p66ShcA levels are associated with the acquisition of an EMT in primary breast cancers spanning all molecular subtypes, including luminal tumors. This is of high clinical relevance, as the luminal and HER2 subtypes together comprise 80% of all newly diagnosed breast cancers. This study identifies p66ShcA as one of the first prognostic biomarkers for the identification of more aggressive tumors with mesenchymal properties, regardless of molecular subtype.
authors: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
authors: Jesse
authors: J
authors: Hudson
authors: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
authors: Jacqueline R
authors: JR
authors: Ha
authors: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
authors: Valerie
authors: V
authors: Sabourin
authors: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
authors: Ryuhjin
authors: R
authors: Ahn
authors: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
authors: Rachel
authors: R
authors: La Selva
authors: Goodman Cancer Research Centre, Montreal, Quebec, Canada.
authors: Julie
authors: J
authors: Livingstone
authors: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
authors: Lauren
authors: L
authors: Podmore
authors: Goodman Cancer Research Centre, Montreal, Quebec, Canada.
authors: Jennifer
authors: J
authors: Knight
authors: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada Goodman Cancer Research Centre, Montreal, Quebec, Canada.
authors: Laura
authors: L
authors: Forrest
authors: Goodman Cancer Research Centre, Montreal, Quebec, Canada Department of Oncology, McGill University, Montreal, Quebec, Canada Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors: Nicole
authors: N
authors: Beauchemin
authors: Goodman Cancer Research Centre, Montreal, Quebec, Canada Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors: Michael
authors: M
authors: Hallett
authors: Goodman Cancer Research Centre, Montreal, Quebec, Canada Department of Oncology, McGill University, Montreal, Quebec, Canada Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors: Morag
authors: M
authors: Park
authors: Lady Davis Institute for Medical Research, Montreal, Quebec, Canada Department of Oncology, McGill University, Montreal, Quebec, Canada giuseppina.ursini-siegel@mcgill.ca.
authors: Josie
authors: J
authors: Ursini-Siegel
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D016513:Mice, SCID; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D014408:Biomarkers, Tumor; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C528024:SHC1 protein, human; C508053:ERBB2 protein, human; C491743:MET protein, human