Transcription Factor p73 Is a Predictor of Platinum Resistance and Promotes Aggressive Epithelial Ovarian Cancers.

Overview

abstract

Resistance to platinum-based chemotherapy is a major clinical problem in ovarian cancers. The development of predictive biomarkers and therapeutic approaches is an area of unmet need. p73, a member of the p53 family of transcription factors, has essential functions during DNA repair, proliferation, invasion, and apoptosis. The role of p73 in ovarian cancer pathogenesis and response to therapy is largely unknown. The clinicopathological significance of p73 protein expression was evaluated in 278 human ovarian cancers. TP73 transcripts were investigated in publicly available clinical data sets (n = 522) and bioinformatics analysis was completed in the ovarian TCGA cohort (n = 182). Preclinically, p73 was overexpressed in A2780 platinum-sensitive ovarian cancer cells or depleted in platinum-resistant A2780cis cells and investigated for aggressive phenotypes, as well as platinum sensitivity. High p73 protein expression was linked with high grade (p < 0.001), advanced-stage disease (p = 0.002), and shorter progression-free survival (p < 0.0001). TP73 transcripts were significantly higher in tumours compared to normal tissue (p < 0.0001) and linked with shorter PFS (p = 0.047). Preclinically, p73 overexpression in A2780 cells increased proliferation, invasion, spheroid formation, and DNA repair capacity, and was associated with the upregulation of multiple DNA repair and platinum resistance-associated genes. In contrast, p73 deletion in A2780cis led to reduced proliferation and enhanced sensitivity to cisplatin, along with DNA double-strand break accumulation, G2/M cell cycle arrest, and increased apoptosis. We conclude that p73 is a predictor of platinum resistance. p73 can be exploited for targeted ovarian cancer therapy.