Receptor tyrosine kinase signaling favors a protumorigenic state in breast cancer cells by inhibiting the adaptive immune response

Josie Ursini-Siegel, Sean Cory, Dongmei Zuo, William R. Hardy, Elton Rexhepaj, Sonya Lam, Babette Schade, Karin Jirstrom, Eva Bjur, Ciriaco A. Piccirillo, David DeNardo, Lisa M. Coussens, Donal J. Brennan, William M. Gallagher, Morag Park, Tony Pawson, Michael Hallett, William J. Muller

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Using transgenic mouse models of breast cancer that ablate Src homology and collagen A (ShcA) expression or oncogene-coupled ShcA signaling, we previously showed that this adaptor is critical for mammary tumor onset and progression. We now provide the first evidence that ShcA regulates mammary tumorigenesis, in part, through its ability to regulate the adaptive immune response. Inactivation of ShcA signaling within tumor cells results in extensive CD4+ T-cell infiltration and induction of a humoral immune response in mammary tumors. This is associated with a robust CTL response in preneoplastic lesions that are deficient in ShcA signaling. Moreover, mammary tumor progression of ShcA-deficient hyperplasias is accelerated in a T cell - deficient background. We also uncover a clinically relevant correlation between high ShcA expression and low CTL infiltration in human breast cancers. Finally, we define a novel ShcA-regulated immune signature that functions as an independent prognostic marker of survival in human epidermal growth factor receptor 2+ and basal breast cancers. We reveal a novel role for tumor cell - derived ShcA in the establishment and maintenance of an immunosuppressive state.

Original languageEnglish (US)
Pages (from-to)7776-7787
Number of pages12
JournalCancer Research
Volume70
Issue number20
DOIs
StatePublished - Oct 15 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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