Activation of ER alpha Signaling Differentially Modulates IFN-gamma Induced HLA-Class II Expression in Breast Cancer Cells

作者：Mostafa Ahmed A; Codner Dianne; Hirasawa Kensuke; Komatsu Yumiko; Young Matthew N; Steimle Viktor; Drover Sheila^*

来源：PLos One, 2014, 9(1): e87377.

DOI：10.1371/journal.pone.0087377

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-gamma levels, reduced expression of the estrogen receptor (ER) and reduced age at diagnosis. Here, we tested the hypothesis that estradiol (E-2) and ER alpha signaling contribute to the regulation of IFN-gamma inducible HLA-II in breast cancer cells. Using a panel of established ER- and ER+ breast cancer cell lines, we showed that E-2 attenuated HLA-DR in two ER+ lines (MCF-7 and BT-474), but not in T47D, while it augmented expression in ER 2 lines, SK-BR-3 and MDA-MB-231. To further study the mechanism(s), we used paired transfectants: ER alpha(+) MC2 (MDA-MB-231 c10A transfected with the wild type ER alpha gene) and ER alpha(-) VC5 (MDA-MB-231 c10A transfected with the empty vector), treated or not with E-2 and IFN-gamma. HLA-II and CIITA were severely reduced in MC2 compared to VC5 and were further exacerbated by E-2 treatment. Reduced expression occurred at the level of the IFN-gamma inducible CIITA promoter IV. The anti-estrogen ICI 182,780 and gene silencing with ESR1 siRNA reversed the E-2 inhibitory effects, signifying an antagonistic role for activated ER alpha on CIITA pIV activity. Moreover, STAT1 signaling, necessary for CIITA pIV activation, and selected STAT1 regulated genes were variably downregulated by E-2 in transfected and endogenous ER alpha positive breast cancer cells, whereas STAT1 signaling was noticeably augmented in ER alpha(-) breast cancer cells. Collectively, these results imply immune escape mechanisms in ER alpha(+) breast cancer may be facilitated through an ER alpha suppressive mechanism on IFN-gamma signaling.

• 出版日期2014-1-27