Abstract
Resistance to tamoxifen is a clinically major challenge in breast cancer treatment. Although downregulation of estrogen receptor‐alpha (ERα) is the dominant mechanism of tamoxifen resistance, the reason for ERα decrease during tamoxifen therapy remains elusive. Herein, we reported that Spalt‐like transcription factor 2 (SALL2) 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. SALL2 transcriptionally upregulated ESR1 and PTEN through directly binding to the DNA promoters. By contrast, silencing SALL2 induced downregulation of ERα and PTEN and activated the Akt/mTOR signaling, resulting in estrogen‐independent growth and tamoxifen resistance in ERα‐positive breast cancer. Furthermore, hypermethylation of SALL2 promoter was found in tamoxifen‐resistant breast cancer. Importantly, in vivo experiments showed that DNA methyltransferase inhibitor‐mediated SALL2 restoration resensitized tamoxifen‐resistant breast cancer to tamoxifen therapy. These findings shed light on the mechanism of SALL2 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.
Highlights
Endocrine therapies, including selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and selective estrogen receptor downregulators (SERDs), are the mainstay of treatments for estrogen receptor-alpha (ERa)-positive (ER+) breast cancer, which accounts for approximately 70% of all breast cancers (Musgrove & Sutherland, 2009)
We found that ESR1 mRNA levels were downregulated in eight out of nine relapsed lesions compared to their corresponding primary tumors (Figs 1B and EV1A and B), which provided additional evidence that ESR1 was transcriptionally repressed during tamoxifen therapy
We further found that the transcription factor Spalt-like transcription factor 2 (SALL2) was downregulated during tamoxifen therapy via profiling of 9 paired breast cancer tissues
Summary
Endocrine therapies, including selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and selective estrogen receptor downregulators (SERDs), are the mainstay of treatments for estrogen receptor-alpha (ERa)-positive (ER+) breast cancer, which accounts for approximately 70% of all breast cancers (Musgrove & Sutherland, 2009). Tamoxifen therapy has a beneficial effect on survival time and reduces recurrent events in breast cancer patients (Cuzick et al, 2007), approximately 30–40% of patients with breast cancer receiving adjuvant tamoxifen therapy still relapse or progress to deadly advanced metastatic stages within 15 years of follow-up (EBCTC, 1998; EBCTC et al, 2011). It is well established that ER expression level is a determinant of tamoxifen response in ER+ breast cancer, and loss of ER expression is a crucial factor contributing to tamoxifen resistance (Musgrove & Sutherland, 2009; Osborne & Schiff, 2011). The transcriptional levels of ESR1 are significantly decreased in relapsed lesions compared with primary tissues in tamoxifen-treated breast cancer
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