Abstract A32: PBX1, a transcriptional regulator, promotes stemness and chemoresistance in ovarian cancer.

Abstract

Abstract Background: Cancer recurrence and chemoresistance contribute greatly to the high mortality of ovarian cancers; however, molecular players involved in these processes remain under-determined. Several theories have been proposed to account for the development of resistance to chemotherapeutic agents. One of the emerging concepts is tumor heterogeneity, which argues for the presence of different cell subpopulations in bulk tumor with varying degrees of tumor initiating potential and drug sensitivity. The fractions of cells with enhanced tumor initiating potential are referred to as cancer stem-like cells (CSC). These cells have defining “stemness” phenotypes, including unlimited cell division, repopulation by a minimum cell number and resistance to cytotoxic agents and irradiation. New Findings: To identify embryonic stem cell factors that are potentially involved in tumor recurrence and chemoresistance, we have screened expression levels of four of these factors by immunohistochemistry in pairs of matched recurrent and primary tumor tissues from 41 patients. Our data demonstrated that PBX1 is significantly up-regulated in recurrent/chemoresistant ovarian tumors. Moreover, PBX1 overexpression in ascites tumors correlates with shorter overall survival in post-chemotherapy ovarian cancer patients. When PBX1 is ectopically expressed, it promotes cancer stem cell-like phenotypes, including increased side population and ALDH1 activity, enhanced tumorigenicity at low cell density, and increased resistance to platinum-based therapy. In platinum-resistant cell lines that overexpress PBX1, silencing PBX1 expression using RNA interference sensitizes cells to platinum treatment and reduces their stem cell-like phenotypes. Gene expression and chromatin immunoprecipitation analyses identified PBX1 direct target genes involved in multi-drug resistance, stem cell maintenance, immunomodulation, and DNA damage response. In the TCGA ovarian cancer recurrent series, expression of several PBX1 direct target genes, including ABCA1, Nanog, BMP3, and ATM, is tightly associated with PBX1 expression, further supporting the tissue-level transcriptional regulation of these genes by PBX1. Conclusion: The above findings establish PBX1 as an upstream regulator of key functional networks that mediate cancer stem-like and drug resistant phenotypes. Studies on the hematopoietic system have indicated that PBX1 maintains a viable pool of quiescent stem cells. Recently, in a renal cell carcinoma system, chemotherapy has been shown to induce damage signaling and to stimulate cell division and repopulation of quiescent CSCs. We speculate that chemotherapy in ovarian cancer may induce comparable injury responses and trigger PBX1 signaling, which in turn may activate downstream networks that support CSC survival and create a microenvironment niche that is essential for CSC repopulation at the tissue level. Collectively, the association between PBX1 and a cascade of stemness pathways points to a potential Achilles's heel critical to responding to chemotherapy and developing chemoresistance and argues for the development of antagonists of PBX1 signaling as anticancer agents. Citation Format: Jin-Gyoung Jung, Tae-Hoen Kim, Emily Gerry, Jen-Chun Kuan, Ayse Ayhan, Ben Davidson, Ie-Ming Shih, Tian-Li Wang. PBX1, a transcriptional regulator, promotes stemness and chemoresistance in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A32.