Abstract 4322: EXOSC4, a novel gene at chromosome 8q24 loci is linked with breast cancer progression and is a prognostic marker for breast cancer survival

Abstract

Abstract The chromosome 8q24 gene contains functional risk loci for multiple cancers, including prostate, colon, and breast. Breast cancer (BrCa) is one of the deadliest diseases among women. Our previous studies using TCGA clinical survival data (Cell. 2018; 173(2):400-416.e11) indicated that several genes are contributed significantly towards the survival of patients with BrCa. Over 75 such most significant genes were screened for further studies in terms of their contribution towards BrCa patient's survival. We found two genes (EXOSC4 and VPS28) with over 10% genetic copy number alterations located at chromosome 8q24 gene loci. Exosome Component 4 (EXOSC4) is located at 8q24.3 and associated with a non-catalytic component of the RNA exosome complex, which has 3' to 5' exoribonuclease activity. It also participates in cellular RNA processing and degradation events. However, the functional role of EXOSC4 towards BrCa progression or survival remains unknown. To understand the molecular basis of an elevated level of EXOSC4 in BrCa propagation, we screened the expression of this protein in different BrCa cell-lines. We also compared the expression of VPS28 within same cell lines. Data indicated that EXOSC4 was co-expressed with VPS28 and Myc, and was also secreted into extracellular space. Therefore, we next evaluated the level of EXOSC4 in patient's serum samples by reverse phase protein array (RPPA). We have well defined and categorized BrCa patients serum samples (n=240) from the Clinical Breast Care Project. The data indicated that the elevated level of EXOSC4 is associated with worse overall survival. In addition, results also showed that the high level of EXOSC4 is linked with breast cancer recurrence.In summary, through multiple modality studies we have confirmed the copy number alteration of EXOSC4 is associated with BrCa patient survival. Once validated, serum level of EXOSC4 could be a predictive biomarker for BrCa progression and survival. Additional experiments are ongoing to evaluate the regulatory role of the EXOSC4 gene which has the potential to develop into a novel therapeutic intervention of BrCa. Funding Sources: This work was supported by the grant to Dr. Meera Srivastava (DoD, DAMD17-03-1-0107). The work was also supported by the Collaborative Health Initiative Research Program (CHIRP) funding (CHIRP ID# IAA-A-HL-14-007). Disclaimers: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of The Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation (HJF), the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. Correspondence: Email: meera.srivastava@usuhs.edu Citation Format: Alakesh Bera, John Karaian, Madhan Subramanian, Michael Eklund, Eric Russ, Harvey B. Pollard, Hai Hu, Craig D. Shriver, Meera Srivastava. EXOSC4, a novel gene at chromosome 8q24 loci is linked with breast cancer progression and is a prognostic marker for breast cancer survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4322.