Activation of ERα Signaling Differentially Modulates IFN-γ Induced HLA-Class II Expression in Breast Cancer Cells

Abstract

The coordinate regulation of HLA class II (HLA-II) is controlled by the class II transactivator, CIITA, and is crucial for the development of anti-tumor immunity. HLA-II in breast carcinoma is associated with increased IFN-γ levels, reduced expression of the estrogen receptor (ER) and reduced age at diagnosis. Here, we tested the hypothesis that estradiol (E2) and ERα signaling contribute to the regulation of IFN-γ inducible HLA-II in breast cancer cells. Using a panel of established ER− and ER+ breast cancer cell lines, we showed that E2 attenuated HLA-DR in two ER+ lines (MCF-7 and BT-474), but not in T47D, while it augmented expression in ER− lines, SK-BR-3 and MDA-MB-231. To further study the mechanism(s), we used paired transfectants: ERα+ MC2 (MDA-MB-231 c10A transfected with the wild type ERα gene) and ERα− VC5 (MDA-MB-231 c10A transfected with the empty vector), treated or not with E2 and IFN-γ. HLA-II and CIITA were severely reduced in MC2 compared to VC5 and were further exacerbated by E2 treatment. Reduced expression occurred at the level of the IFN-γ inducible CIITA promoter IV. The anti-estrogen ICI 182,780 and gene silencing with ESR1 siRNA reversed the E2 inhibitory effects, signifying an antagonistic role for activated ERα on CIITA pIV activity. Moreover, STAT1 signaling, necessary for CIITA pIV activation, and selected STAT1 regulated genes were variably downregulated by E2 in transfected and endogenous ERα positive breast cancer cells, whereas STAT1 signaling was noticeably augmented in ERα− breast cancer cells. Collectively, these results imply immune escape mechanisms in ERα+ breast cancer may be facilitated through an ERα suppressive mechanism on IFN-γ signaling.

Expression of the MHC Class II Pathway in Triple-Negative Breast Cancer Tumor Cells Is Associated with a Good Prognosis and Infiltrating Lymphocytes

“…5). This result confirms previous reports(41, 45, 46) that TNBC tumor cells can express components of the MHC class II antigen presentation pathway and demonstrates that induction of this pathway can occur through the same signaling pathway that activates APCs.…”

Promoter Methylation Modulates Indoleamine 2,3-Dioxygenase 1 Induction by Activated T Cells in Human Breast Cancers

“…Activation of ERα signaling was reported to attenuate IFNγ-induced expression of HLA class II genes such as CIITA and HLA-DR in ER + BC cell lines (46). However, careful examination of the IDO1 promoter sequence failed to identify valid estrogen response elements (EREs) and analysis of the ERα ChIP-seq data set in the ENCODE database also did not reveal any ERα binding event in IDO1 locus in estradiol-treated MCF7 and T47D cells.…”

Adaptive Immune Regulation of Mammary Postnatal Organogenesis

“…Moreover, in an estrogen receptor (ER) α+ luminal type human breast cancer model which is heavily infiltrated by innate immune cells and T lymphocytes (Bos et al, 2013), IFNγ and CD4+ T cells (but not NK or CD8+ T cells) show anti-tumor activity and inhibit metastatic tumor progression via extensive apoptotic tumor cell death. Other studies imply that immune escape mechanisms in ERα+ breast cancer may be facilitated through an ERα suppressive mechanism on IFNγ signaling (Mostafa et al, 2014). Indeed, in a mouse model of human epidermal growth factor receptor (HER) 2-positive breast cancers, tumor cells control the outcome of tumor immune surveillance through modulation of IFNγR1 expression on tumor cells.…”