Abstract 804: Class II transactivator (CIITA) transcription is reduced by the ER-E2 signaling pathway in breast cancer cells

Abstract

Abstract The immune response is regulated by the interaction of CD4+T-cells with human leukocyte antigen class II (HLA-II). HLA-II genes code for HLA-DR that display peptides from antigens, which have undergone proteolysis in the endocytic pathway. Peptide loading of HLA-DR molecules also requires the co-chaperones; Invariant chain (Ii) and HLA-DM. Regulation of HLA-II occurs mainly at the transcription level, through interaction of transcription factors with the class II transactivator (CIITA). We previously reported that discordant expression of HLA-II in breast cancer associated with decreased estrogen receptor (ER) levels and younger age at diagnosis, suggesting that the estrogen-ER signaling pathway is implicated in regulating HLA-II in breast carcinoma cells. Moreover, using an experimental model of ER+ and ER− breast cancer cell lines, we found that estradiol (E2) augmented expression in the ER− cell line but decreased expression in the ER+ transfectant. To address whether ER and E2 interfere with CIITA expression, we performed Western blotting and quantitative real-time PCR in the same experimental cell system. CIITA expression was markedly reduced in ER+, but not in ER− cells; furthermore, CIITA inversely correlated with ER levels. CIITA promoter activity was analysed using a luciferase reporter gene construct in cell lines, treated or not with E2 and/or ICI 182,780 (ER antagonist). CIITA luciferase activity was reduced in ER+ cells and was further inhibited by E2 and was restored by ICI. This suggests that ER may be recruited to the CIITA promoter and indirectly interfere with transcription of HLA-II genes. We further analyzed HLA-II in a wild type ER+ line, MCF-7, which was stimulated with IFN-γ or stably transfected with CIITA. HLA-DR surface expression, ascertained by flow cytometry, was upregulated in cells grown in E2-depleted medium. Western blotting confirmed that ER degradation by ICI in MCF-7 correlated with up regulation of CIITA and HLA-II. In aggregate, these results indicate that the E2-ER pathway interferes with CIITA and HLA-II expression. Investigations such as this should improve our understanding of how ER and estrogen modulate the antigen presentation capabilities and immune recognition of breast cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 804. doi:10.1158/1538-7445.AM2011-804