Dr. Sheila Drover - Nov. 23, 2012

Estradiol-modulation of HLA-II in human breast cancer cells

Immune responses, including those against antigens on tumour cells, require antigen to be processed into peptides, loaded onto HLA-II molecules by the peptide editor, HLA-DM, and subsequently presented at the cell surface for CD4+ T-cell recognition. Although HLA-II molecules are not normally expressed on epithelial cells, they can be induced by exposure to interferon-gamma (IFN-γ), which may explain the increased frequency of HLA-DR (a type of HLA-II molecule) on some tumour cells. Our laboratory previously showed that co-ordinate expression of HLA-DR and HLA-DM on tumour cells in human breast carcinoma tissues associated with high levels of IFN-γ and increased survival. Interestingly, estrogen receptor negative (ER-) tumours from younger women more frequently expressed HLA-DR than did ER+ tumours from older women. Since breast tumours contain high levels of estradiol, irrespective of menopausal status, these observations implied that estradiol negatively regulates HLA-DR expression in ERα+ but not in ERα- tumour cells. To test this hypothesis in an experimental model, we analyzed IFN-γ inducible HLA-II in breast cancer cell lines (BCCL) including paired ERα(MC2) and vector (VC5) transfected MDA-MB-231 in the presence and absence of estradiol (E2) and/or anti-estrogens. We found: i) E2-treatment significantly diminished IFN-γ inducible HLA-II and the master regulator of HLA-II expression, CIITA, in the ERα+ MC2 line but not in the ERα- VC5 line; ii) depletion of ERα in MC2 by the antiestrogen, ICI or by siRNA reversed the E2-mediated effect on HLA-II expression, CIITA promoter activity and transcriptional activation of CIITA; iii) various components of the IFN-γ pathway were disrupted in E2-treated ERα+ cells, but not in ERα- cells. Altogether, these results suggest that E-activation of ERα negatively regulates HLA-II expression in breast cancer cells by interfering with IFN-γ signalling. However, the mechanism by which this occurs remains to be elucidated and is the focus of current and future studies.



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