Abstract 4225: Estrogen regulated oncogene SHON mediates the efficacy of anti-estrogen treatment in breast cancer

Abstract

Abstract Background: Estrogen receptors (ER) play a pivotal role in the etiology and progression of breast cancer. Hormone receptor positive breast cancers usually respond to endocrine therapy at the beginning, but a substantial proportion will eventually develop anti-estrogen resistance. However, the mechanism remains largely unclear. Cross-talk between ER and growth factor signaling pathways is known to contribute to the development of anti-estrogen resistance. In addition, activation of JNK signaling pathway has been implicated in tamoxifen resistance of mammary carcinoma MCF-7 cells. We have demonstrated that SHON is a novel human oncogene and its expression is inducible by estradiol (E2). Moreover, SHON expression is highly positively correlated with ER, progesterone receptor (PR) and androgen receptor (AR) expression in breast cancer, and may also serve as a prognostic biomarker for predicting patient response to anti-estrogen therapy in ER+ breast cancer. Purpose: This study aimed to investigate how SHON modulated estrogen signaling and its role in anti-estrogen treatment and resistance in ER+ breast cancer. Methods: Estrogen responsive luciferase reporter assays were used to measure the activation of ER signaling by SHON. Total cell number and soft agar colony formation assays were used to determine the effects of SHON expression on the efficacy of anti-estrogens. Protein expression was measured by Western blotting. Results: Forced expression of SHON in MCF-7 cells increased ER transcriptional activity while depletion of endogenous SHON decreased this activity. Upon tamoxifen or fulvestrant treatment, MCF-7 cells stably transfected with SHON expression plasmid displayed an increase in total cell number and cell migration compared with the control vector transfected MCF-7 cells. Anti-estrogen treatment inhibited the colony formation of MCF-7 cells in soft agar, and this inhibitory effect was significantly abrogated by forced expression of SHON. SHON also increased the protein level of both ERα and JNK in MCF-7 cells under estrogen deprivation or stimulation, or under estrogen stimulation in combination with tamoxifen or fulvestrant treatment. Conclusion: There was a positive feedback of SHON and ERα expression. SHON may mediate the efficacy of anti-estrogen drugs via modulation of ERα and JNK expression. These results improve our understanding of the role of SHON in anti-estrogen treatment and provide evidence for the use of SHON antagonism in enhancing the efficacy of anti-estrogen treatment. Citation Format: Bing Xu, Yewon Jung, Jo Perry, Tao Zhu, Peter E. Lobie, Baiqu Huang, Jun Lu, Dong-Xu Liu. Estrogen regulated oncogene SHON mediates the efficacy of anti-estrogen treatment in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4225. doi:10.1158/1538-7445.AM2014-4225