Abstract P4-04-18: Estrogen receptor α-dependent transcriptional induction of selenium-binding protein 1 increases the sensitivity of tamoxifen treatment in breast cancer

Abstract

Abstract Reduction of selenium-binding protein 1 (SELENBP1) has been frequently observed in various solid tumors, and associated with poor clinical prognosis, implicating SELENBP1 as a potential tumor suppressor. However, the molecular mechanism underlying the transcriptional regulation of SELENBP1 remains poorly understood. In this study, we first analyzed the relationship between SELENBP1 mRNA levels and clinical or pathological features of breast cancer in METABRIC datasets, and found that SELENBP1 mRNA levels were differentially expressed in PAM50 molecular subtypes with highest levels in Luminal A/B subtype and lowest levels in Basal-like/Claudin-low subtype, indicating that SELENBP1 might function as the downstream player of estrogen receptor α (ERα). Following the adjustment of clinicopathological characteristics including the menopausal status, ER/HR/ERBB2 status, TNM stage and histological grade, the Kaplan-Meier survival analysis surprisingly showed that patients with higher levels of SELENBP1 mRNA (n=43) had shorter survival time than those with moderate levels of SELENBP1 expression (n=102) in Luminal A subtype (Hazard Ratio 1.59; 95% CI 0.99-2.54; Logrank p=0.0367), although the patients with lower SELENBP1 levels were consistent the poor prognosis in Basal-like/Claudin-low subtype (Hazard Ratio 1.54; 95% CI 0.97-2.44; Logrank p=0.0356). To elucidate this controversy, we knocked down the expression of ERα in MCF-7 cells using shRNA targeting ERα, and found that knockdown of ERα resulted in the down-regulation of mRNA and protein expression of SELENBP1. In addition, SELENBP1 promoter-driven luciferase reporter assay reveled ERα regulated the expression of SELENBP1 at transcriptional level. Interestingly, we further found that the addition of 4-hydroxytamoxifen (4-OHT) led to a dramatic reduction of SELENBP1 protein expression in MCF-7 cells, while forced expression of SELENBP1 in MCF-7 cells significantly enhanced 4-OHT-mediated inhibition of anchor-independent cancer cell growth. Collectively, these results suggested that the transcriptional induction of SELENBP1 by ERα might function as a downstream tumor suppressor in breast cancer cells, but endocrine therapy led to the down-regulation of SELENBP1 expression due to the blocking of ERα signaling in the patients with Luminal subtype, which was likely to explain the observation of differential predictive value for SELENBP1 mRNA levels in the Luminal and Basal-like/Claudin-low subtypes. Further investigation in vitro and in vivo has been ongoing in our laboratory, and the results from which will help us better understand the clinical relevance for SELENBP1 as a promising therapeutic target in improving the efficacy of endocrine therapy. This study was supported in part by National Natural Science Foundation of China (8160111571) and Guangdong Natural Science Foundation (2016A030313768). Citation Format: Liao N, Wang Y, Zhang G, Cao L, Li K, Ren C-Y, Wen L-Z, Shi Y, Zhu W, Chen X. Estrogen receptor α-dependent transcriptional induction of selenium-binding protein 1 increases the sensitivity of tamoxifen treatment in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-18.