Stat1 Facilitates Oestrogen Receptor Alpha Transcription And Stimulates Breast Cancer Cell Proliferation

Oestrogen receptor alpha (ER alpha) is overexpressed in two-thirds of all breast cancer cases and is involved in breast cancer development and progression. Although ER alpha -positive breast cancer can be effectively treated by endocrine therapy, endocrine resistance is an urgent clinical problem. Thus, further understanding of the underlying mechanisms involved in ER alpha signalling is critical in dealing with endocrine resistance in patients with breast cancer. In the present study, unbiased RNA sequence analysis was conducted between the MCF-7 and MCF-7 tamoxifen-resistant (LCC2) cell lines in order to identify differentially expressed genes. The whole transcriptomic data indicated that the JAK-STAT pathway is markedly up-regulated, particularly the ISGF3 complex. As the critical effectors, STAT1 and IRF9 were up-regulated 5- and 20-fold, respectively, in LCC2 cells. The biological experiments indicated that STAT1 is important for ER alpha signalling. Depletion of STAT1 or inhibition of STAT1 function significantly decreased levels of ER alpha protein, ER alpha -target gene expression and cell proliferation in both the MCF-7 and LCC2 cell lines. Chromatin immunoprecipitation revealed that ER alpha transcription is associated with STAT1 recruitment to the ER alpha promoter region, suggesting that transcriptional regulation is one mechanism by which STAT1 regulates ER alpha mRNA levels and ER alpha signalling in breast cancer cells. The present study reveals a possible endocrine-resistant mechanism by which STAT1 modulates ER alpha signalling and confers tamoxifen resistance. Targeting of STAT1 is a potential treatment strategy for endocrine-resistant breast cancers.