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Signal Transduction

Integration of Distinct ShcA Signaling Complexes Promotes Breast Tumor Growth and Tyrosine Kinase Inhibitor Resistance

Jacqueline R. Ha, Ryuhjin Ahn, Harvey W. Smith, Valerie Sabourin, Steven Hébert, Eduardo Cepeda Cañedo, Young Kyuen Im, Claudia L. Kleinman, William J. Muller and Josie Ursini-Siegel
Jacqueline R. Ha
Lady Davis Institute for Medical Research, Montréal, Quebec, Canada.Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada.
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Ryuhjin Ahn
Lady Davis Institute for Medical Research, Montréal, Quebec, Canada.Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada.
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Harvey W. Smith
Department of Biochemistry, McIntyre Medical Building, McGill University, Montréal, Quebec, Canada.Goodman Cancer Research Centre, Montréal, Quebec, Canada.
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Valerie Sabourin
Lady Davis Institute for Medical Research, Montréal, Quebec, Canada.
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Steven Hébert
Lady Davis Institute for Medical Research, Montréal, Quebec, Canada.
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Eduardo Cepeda Cañedo
Lady Davis Institute for Medical Research, Montréal, Quebec, Canada.Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada.
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Young Kyuen Im
Lady Davis Institute for Medical Research, Montréal, Quebec, Canada.Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada.
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Claudia L. Kleinman
Lady Davis Institute for Medical Research, Montréal, Quebec, Canada.Department of Human Genetics, Strathcona Anatomy & Dentistry Building, McGill University, Montréal, Quebec, Canada.
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William J. Muller
Department of Biochemistry, McIntyre Medical Building, McGill University, Montréal, Quebec, Canada.Department of Human Genetics, Strathcona Anatomy & Dentistry Building, McGill University, Montréal, Quebec, Canada.
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Josie Ursini-Siegel
Lady Davis Institute for Medical Research, Montréal, Quebec, Canada.Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada.Department of Biochemistry, McIntyre Medical Building, McGill University, Montréal, Quebec, Canada.Goodman Cancer Research Centre, Montréal, Quebec, Canada.Gerald Bronfman Department of Oncology, McGill University, Montréal, Quebec, Canada.
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  • For correspondence: giuseppina.ursini-siegel@mcgill.ca
DOI: 10.1158/1541-7786.MCR-17-0623
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Abstract

The commonality between most phospho-tyrosine signaling networks is their shared use of adaptor proteins to transduce mitogenic signals. ShcA (SHC1) is one such adaptor protein that employs two phospho-tyrosine binding domains (PTB and SH2) and key phospho-tyrosine residues to promote mammary tumorigenesis. Receptor tyrosine kinases (RTK), such as ErbB2, bind the ShcA PTB domain to promote breast tumorigenesis by engaging Grb2 downstream of the ShcA tyrosine phosphorylation sites to activate AKT/mTOR signaling. However, breast tumors also rely on the ShcA PTB domain to bind numerous negative regulators that limit activation of secondary mitogenic signaling networks. This study examines the role of PTB-independent ShcA pools in controlling breast tumor growth and resistance to tyrosine kinase inhibitors. We demonstrate that PTB-independent ShcA complexes predominately rely on the ShcA SH2 domain to activate multiple Src family kinases (SFK), including Src and Fyn, in ErbB2-positive breast cancers. Using genetic and pharmacologic approaches, we show that PTB-independent ShcA complexes augment mammary tumorigenesis by increasing the activity of the Src and Fyn tyrosine kinases in an SH2-dependent manner. This bifurcation of signaling complexes from distinct ShcA pools transduces non-redundant signals that integrate the AKT/mTOR and SFK pathways to cooperatively increase breast tumor growth and resistance to tyrosine kinase inhibitors, including lapatinib and PP2. This study mechanistically dissects how the interplay between diverse intracellular ShcA complexes impacts the tyrosine kinome to affect breast tumorigenesis.

Implications: The ShcA adaptor, within distinct signaling complexes, impacts tyrosine kinase signaling, breast tumor growth, and resistance to tyrosine kinase inhibitors. Mol Cancer Res; 1–15. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Received October 25, 2017.
  • Revision received December 20, 2017.
  • Accepted January 26, 2018.
  • Published first February 16, 2018.
  • ©2018 American Association for Cancer Research.

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Published OnlineFirst April 5, 2018
doi: 10.1158/1541-7786.MCR-17-0623

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Integration of Distinct ShcA Signaling Complexes Promotes Breast Tumor Growth and Tyrosine Kinase Inhibitor Resistance
Jacqueline R. Ha, Ryuhjin Ahn, Harvey W. Smith, Valerie Sabourin, Steven Hébert, Eduardo Cepeda Cañedo, Young Kyuen Im, Claudia L. Kleinman, William J. Muller and Josie Ursini-Siegel
Mol Cancer Res April 5 2018 DOI: 10.1158/1541-7786.MCR-17-0623

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Integration of Distinct ShcA Signaling Complexes Promotes Breast Tumor Growth and Tyrosine Kinase Inhibitor Resistance
Jacqueline R. Ha, Ryuhjin Ahn, Harvey W. Smith, Valerie Sabourin, Steven Hébert, Eduardo Cepeda Cañedo, Young Kyuen Im, Claudia L. Kleinman, William J. Muller and Josie Ursini-Siegel
Mol Cancer Res April 5 2018 DOI: 10.1158/1541-7786.MCR-17-0623
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Molecular Cancer Research
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