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

Cancer Res. 2010 Oct 15;70(20):7776-87. doi: 10.1158/0008-5472.CAN-10-2229. Epub 2010 Oct 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • CD4-Positive T-Lymphocytes / pathology
  • Female
  • Humans
  • Immunosuppression Therapy
  • Mammary Neoplasms, Experimental / immunology
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Parity
  • Pregnancy
  • Proportional Hazards Models
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / isolation & purification
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Shc Signaling Adaptor Proteins / deficiency
  • Shc Signaling Adaptor Proteins / genetics*
  • Shc Signaling Adaptor Proteins / physiology
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Treatment Outcome


  • RNA, Neoplasm
  • Shc Signaling Adaptor Proteins
  • Receptor Protein-Tyrosine Kinases