Abstract 3441: A RPL39-SGK3 signaling pathway that may play a key role in breast cancer therapy resistance

Abstract

Abstract Breast cancer is the most common cancer in the United States, where 1 in 8 women are affected by it during their lifetime. In 2018, an estimated 266,120 new cases of invasive breast cancer are expected to be diagnosed in women in the U.S., along with 63,960 new cases of non-invasive (in situ) breast cancer. In order to identify novel targets and better understand the mechanism of survival of these cancers, we describe the mechanism of action of ribosomal protein like 39 (RPL39) as one potentially useful target for therapy resistance. RPL39 is over-expressed in breast cancer and regulated by nitric oxide signaling (NOS). In the present study we examine the detailed mechanism of action of RPL39 as it relates to treatment-resistant breast cancers and the role of SGK3 in modulating its signal transduction pathway. Methods and Results: Mass spectrometric analysis following immunoprecipitation of RPL39, in two breast cancer cell lines SUM159 and MDAMB231, indicated that proteins involved in translation, specifically the mTOR-dependent translational pathway, were part of the complex. In order to verify that the results we observed were due to targeting of the translational arm of mTOR signaling, we knocked down both the 4EBP-1 (translation) and S6K (cell size) arms of the mTOR pathway in three breast cancer cell lines (SUM159, MDAMB231 and MDAMB436). Analysis of these pathways by proliferation, apoptosis, sphere formation and western blotting in all three breast cancer cell lines demonstrated that the translation arm was significantly altered: self-renewal (p<0.05, Student's t test) and proliferation (p<0.05, student's t test) in a NOS signaling dependent manner. Additional bioinformatic analysis determined a potential role for SGK3 upstream of RPL39. SGK3 is an AGC kinase family member that is over-expressed in ER+ breast cancers. It functions downstream of PI 3-kinase and can activate the mTOR pathway. Conclusion: RPL39 gene may be modulated by the selective translational initiation complex which affects self-renewal and proliferation through SGK3 and NOS signaling. The significance of targeting SGK3 and RPL39 pathway allows a potentially novel therapeutic strategy for the treatment of breast cancer. Citation Format: Dan Liu, Bhuvanesh Dave. A RPL39-SGK3 signaling pathway that may play a key role in breast cancer therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3441.