Epigenetic silencing of SALL 2 confers tamoxifen resistance in breast cancer

Resistance to tamoxifen is a clinically major challenge in breast cancer treatment. Although downregulation of estrogen receptor‐alpha ( ER α) is the dominant mechanism of tamoxifen resistance, the reason for ER α decrease during tamoxifen therapy remains elusive. Herein, we reported that Spalt‐like transcription factor 2 ( SALL 2) expression was significantly reduced during tamoxifen therapy through transcription profiling analysis of 9 paired primary pre‐tamoxifen‐treated and relapsed tamoxifen‐resistant breast cancer tissues. SALL 2 transcriptionally upregulated ESR 1 and PTEN through directly binding to the DNA promoters. By contrast, silencing SALL 2 induced downregulation of ER α and PTEN and activated the Akt/ mTOR signaling, resulting in estrogen‐independent growth and tamoxifen resistance in ER α‐positive breast cancer. Furthermore, hypermethylation of SALL 2 promoter was found in tamoxifen‐resistant breast cancer. Importantly, in vivo experiments showed that DNA methyltransferase inhibitor‐mediated SALL 2 restoration resensitized tamoxifen‐resistant breast cancer to tamoxifen therapy. These findings shed light on the mechanism of SALL 2 in regulation of ER and represent a potential clinical signature that can be used to categorize breast cancer patients who may benefit from co‐therapy with tamoxifen and DNMT inhibitor.