The Association of Estrogen Receptor Activity, Interferon Signaling, and MHC Class I Expression in Breast Cancer

Abstract Background: The expression of major histocompatibility complex class I (MHC I) has previously been reported to be negatively associated with estrogen receptor (ER) expression. Furthermore, the expression of MHC I, the level of tumor-infiltrating lymphocytes (TILs), and the expression of interferon (IFN) mediator MxA are positively associated with one another in human breast cancers. This study aimed to investigate the mechanisms of association of MHC I with estrogen and IFN signaling. Methods: The human leukocyte antigen (HLA)-ABC protein expression was analyzed in breast cancer cell lines. The expressions of HLA-A and MxA mRNAs were analyzed in MCF-7 cells in Gene Expression Omnibus (GEO) data. ER and HLA-ABC expressions and TIL levels in tumor tissue were also analyzed in ER+/ human epidermal growth factor receptor 2 (HER2)- breast cancer patients who randomly received either neoadjuvant chemotherapy or estrogen modulator treatment following surgical resection. Results: HLA-ABC protein expression was decreased after β-estradiol treatment or hESR-GFP transfection and increased after fulvestrant or IFN-γ treatment in breast cancer cell lines. In GEO data, HLA-A and MxA expression was increased after ESR1 shRNA transfection. When comparing the two patient groups, ER Allred score was significantly lower and the HLA-ABC expression and TIL levels were significantly higher in the estrogen modulator treated group than the chemotherapy treated group. Conclusion: MHC I expression and TIL levels might be affected by ER pathway modulation and IFN treatment. Further studies elucidating the mechanism of MHC I regulation could suggest a way to boost TIL influx in cancer in a clinical setting.