Ribonuclease H2 Subunit A impacts invasiveness and chemoresistance resulting in poor survivability of breast cancer in ER dependent manner

Ribonuclease H2 subunit A (RNASEH2A), a member of the RNase HII family, acts in DNA replication by mediating removal of lagging-strand Okazaki fragment RNA primers. We explored the roles of RNASEH2A in the prognosis of breast cancer, specifically in relation to proliferation, invasiveness, and sensitivity to cytotoxins of cells in the estrogen receptor (ER)-positive MCF-7 and the ER-negative MDA-MB-231 breast cancer cell lines. We collected 26 datasets from around the world, comprising 7815 accessible cases. In these datasets, we probed the association between expression of RNASEH2A and clinical parameters, primarily by inhibiting the expression of RNASEH2A with siRNAs. Such inhibition inhibited the growth and invasiveness of MCF-7 cells. Independent and pooled Kaplan-Meier and Cox analyses revealed that RNASEH2A overexpression was associated with aggressiveness and poor outcomes in a dose-dependent manner in breast cancers of ER-positive subtypes, but not with ER-negative subtypes. The prognostic performance of RNASEH2A mRNA in ER-positive breast cancer was comparable to that for other gene signatures, such as the 21-gene recurrence score. Overexpression of RNASEH2A was also positively associated with cancer cell resistance to chemotherapy; inhibition of RNASEH2A by siRNA enhanced the chemosensitivity in an in vitro study. Bioinformatic analyses indicated that the ER may modulate RNASEH2A action in mitosis, DNA repair, and differentiation through transcriptional regulation. RNASEH2A may be a useful prognostic and predictive biomarker in ER-positive breast cancer and may serve as a therapeutic target for the treatment of ER-positive breast cancer.

Keywords: Ribonuclease H2 Subunit A (RNASEH2A); bioinformatics; breast cancer; chemoresistance; prognostic biomarker.