Abstract B087: HER-2/neu expression regulates the immune response and tumor senescence in breast cancer

Abstract

Abstract Background: Over-expression of the receptor tyrosine kinase ErbB2 (HER-2) has been widely implicated in malignant transformation, cell survival, motility and invasion in breast cancers. Intermediate expression of HER-2 has been identified in luminal breast cancer stem cells. HER-2 over-expression down regulates major histocompatibility complex class I molecules (MHCI) expression in breast cancer cells. Results: We investigated the expression of HER-2 in various HER-2 expressing cell lines and measured HLA A-2 MHC class I expression. High Her-2 expressing cell lines SKBR3 and SKOVA3 and intermediate expressing cell lines MCF7 demonstrated extremely low HLA A-2 expression, while low Her-2 expressing MDAMB231 demonstrated low HER-2 expression and high HLA A2 expression. Anti-HER-2 CD8 T cells recognize the latter cells but not high or intermediate expressing HER-2 expressing cells. Treatment of intermediate expressing cell lines but not high HER-2 expressing cells with interferon-gamma; (IFN- gamma) and TNF-alpha; result in markedly increased HLA A2 expression and 3 fold increase in CD8 T cell killing of the MCF7 cells. Treatment of high expressing HER-2 cells with trastuzumab but not lapatinib decreased HER-2 expression and combined with IFN-gamma; and TNF-alpha; result in increased HLA- A2 expression and dramatic increase in CD8 T cell recognition. In contrast, high and intermediate HER-2 expressing cells are sensitive to lysis and tumor senescence induction when treated with combinations of IFN-gamma; and TNF-alpha; in a dose dependent manner. Low HER-2 expressing cells are less sensitive to senescence induction. Conclusions: In conclusion, our results establish a potential role for HER-2 in regulating the immune response against breast cancer and suggest that CD8 T cells are more effective in eliminating low and intermediate HER-2 expressing cells while CD4 T cell derived IFN-gamma; and TNF-alpha; together with trastuzumab may be more effective in eliminating high expressing HER-2 breast cancer cells and inducing tumor senescence preventing recurrence. Citation Format: Cinthia Rosemblit, Jessica Cintolo-Gonzalez, Shuwen Xu, Brian J. Czerniecki. HER-2/neu expression regulates the immune response and tumor senescence in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B087.