Role of the Tyrosine Phosphatase SHP-1 and Regulatory T Cells in Breast Cancer

Abstract : Uncontrolled proliferation of tumor cells due to failure of immune-surveillance has been linked to cancer development. Regulatory T cells (Treg) play a critical role in immune tolerance by suppressing immune responses to the body's own antigens. The tyrosine phosphatase SHP-1 is a well-known negative regulator of T cell signaling that also affects the generation of Treg cells. Interestingly, mice with decreased levels of SHP-1 protein show a high occurrence of breast cancer. The objective of the studies proposed in the concept award is to test the hypothesis that the CD4+CD25+ regulatory T cell population plays a role in the increased incidence of breast tumors we have observed in me/+ mice. During the first year of the award, we have characterized transgenic mice expressing a dominant negative mutant of SHP-1 in the T cell lineage. Analyses of these mice have demonstrated a T cell autonomous effect of SHP-1 as assessed by TCR/CD3-mediated hyper-proliferation of the mice expressing the dominant negative mutant compared to non-expressers. Moreover in preliminary data, it was observed that expressers show an increase in CD4+CD25+ Treg cells compared to non-expressers making these transgenic mice a powerful model system to directly test the hypothesis that SHP-1 deficiency promotes the development/onset of breast cancer by increasing the number of regulatory T cells.