SRSF5 modulates tamoxifen resistance in oestrogen receptor-positive breast cancer by regulating BQ323636.1 expression

Abstract

Breast cancer is the most common malignancy in females and the fifth largest contributor to cancer-related mortality locally. Oestrogen receptor-positive (ER+) breast cancer represents the largest subtype, for which tamoxifen has been the mainstay in the domain of endocrine therapy. However, intrinsic and acquired tamoxifen resistance remains a predicament in the management of ER+ breast cancer, with almost up to half of the patients eventually developing distant metastasis despite ongoing tamoxifen treatment, thus driving the disease towards a rapidly deteriorating course. BQ323636.1 (BQ), a splice variant of nuclear receptor co-repressor 2 (NCOR2), was previously identified to be a mediator of tamoxifen resistance in ER+ breast cancer by interfering the corepressor function of NCOR2. This study aimed to delineate the splicing aberrations that may be responsible for the biosynthesis of BQ, with a focus on serine/arginine-rich splicing factors (SRSFs). I demonstrated that the level of BQ is negatively correlated with SRSF5 expression, where knockdown of SRSF5 led to upregulation of BQ in MCF-7 cell line while transient overexpression of SRSF5 rendered downregulation of BQ in LCC-2 cell line. Moreover, via immunohistochemistry studies on primary breast cancer tumour samples from 137 patients, it was confirmed that low levels of SRSF5 expression is associated with BQ overexpression, higher risk of relapse and metastasis as well as poorer overall and disease-specific survival. Furthermore, I attempted to identify whether BQ drives and sustains tamoxifen resistance by inducing endoplasmic reticulum (EnR) stress and activating the Jun N-terminal kinase (JNK) signalling pathway. Transient overexpression of BQ in MCF-7 resulted in upregulation of EnR stress marker GRP78 (BiP) and increased phosphorylation level of JNK. However, inhibition of JNK with JNK inhibitor JNK-IN-8 failed to restore sensitivity towards tamoxifen in LCC-2. Nonetheless, results from this study may provide insights into potential therapeutic strategies to suppress BQ formation and mitigate the downstream effects of BQ so as to overcome tamoxifen resistance in ER+ breast cancer.