STAT1 facilitates oestrogen receptor ? transcription and stimulates breast cancer cell proliferation.

ABSTRACT: Oestrogen receptor ? (ER?) is overexpressed in two-thirds of all breast cancer cases and is involved in breast cancer development and progression. Although ER? -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? 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? signalling. Depletion of STAT1 or inhibition of STAT1 function significantly decreased levels of ER? protein, ER? -target gene expression and cell proliferation in both the MCF-7 and LCC2 cell lines. Chromatin immunoprecipitation revealed that ER? transcription is associated with STAT1 recruitment to the ER? promoter region, suggesting that transcriptional regulation is one mechanism by which STAT1 regulates ER? mRNA levels and ER? signalling in breast cancer cells. The present study reveals a possible endocrine-resistant mechanism by which STAT1 modulates ER? signalling and confers tamoxifen resistance. Targeting of STAT1 is a potential treatment strategy for endocrine-resistant breast cancers.

SUBMITTER: Hou Y 

PROVIDER: S-EPMC6237559 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature