Purpose: 1) To investigate expression of the E3 ligase, RNF126, in human invasive breast cancer (BC) and its links with BC outcomes. 2) To test the hypothesis that RNF126 determines the efficacy of inhibitors targeting the cell cycle checkpoint kinase, CHK1. Experimental Design: A retrospective analysis by immunohistochemistry (IHC) compared RNF126 staining in 110 invasive BC and 78 paired adjacent normal tissues with clinicopathologic data. Whether RNF126 controls CHK1 expression was determined by chromatin immunoprecipitation and a CHK1 promoter driven luciferase reporter. Staining for these two proteins by IHC using tissue microarrays was also conducted. Cell killing/replication stress induced by CHK1 inhibition was evaluated in cells, with or without RNF126 knockdown, by MTT/colony formation, replication stress biomarker immunostaining and DNA fiber assays. Results: RNF126 protein expression was elevated in BC tissue samples. RNF126 was associated with a poor clinical outcome after multivariate analysis and was an independent predictor. RNF126 promotes CHK1 transcript expression. Critically, a strong correlation between RNF126 and CHK1 proteins was identified in BC tissue and cell lines. The inhibition of CHK1 induced a greater cell killing and a higher level of replication stress in BC cells expressing RNF126 compared to RNF126 depleted cells. Conclusions: RNF126 protein is highly expressed in invasive BC tissue. The high expression of RNF126 is an independent predictor of a poor prognosis in invasive BC and is considered a potential biomarker of a cancer's responsiveness to CHK1 inhibitors. CHK1 inhibition targets BC cells expressing higher levels of RNF126 by enhancing replication stress.
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