Rnf126 as a biomarker of a poor prognosis in invasive breast cancer and chek1 inhibitor efficacy in breast cancer cells

Xiaosong Yang, You Pan, Zhaojun Qiu, Zhanwen Du, Yao Zhang, Pengyan Fa, Shashank Gorityala, Shanhuai Ma, Shunqiang Li, Ceshi Chen, Hongbing Wang, Yan Xu, Chunhong Yan, Keri Ruth, Zhefu Ma, Junran Zhang

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7 Scopus citations

Abstract

Purpose: (i) To investigate the expression of the E3 ligase, RNF126, in human invasive breast cancer and its links with breast cancer outcomes; and (ii) to test the hypothesis that RNF126 determines the efficacy of inhibitors targeting the cell-cycle checkpoint kinase, CHEK1. Experimental Design: A retrospective analysis by immunohis-tochemistry (IHC) compared RNF126 staining in 110 invasive breast cancer and 78 paired adjacent normal tissues with clinicopathologic data. Whether RNF126 controls CHEK1 expression was determined by chromatin immunoprecipitation and a CHEK1 promoter driven luciferase reporter. Staining for these two proteins by IHC using tissue microarrays was also conducted. Cell killing/replication stress induced by CHEK1 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 breast cancer tissue samples. RNF126 was associated with a poor clinical outcome after multivariate analysis and was an independent predictor. RNF126 promotes CHEK1 transcript expression. Critically, a strong correlation between RNF126 and CHEK1 proteins was identified in breast cancer tissue and cell lines. The inhibition of CHEK1 induced a greater cell killing and a higher level of replication stress in breast cancer cells expressing RNF126 compared to RNF126 depleted cells. Conclusions: RNF126 protein is highly expressed in invasive breast cancer tissue. The high expression of RNF126 is an independent predictor of a poor prognosis in invasive breast cancer and is considered a potential biomarker of a cancer's responsiveness to CHEK1 inhibitors. CHEK1 inhibition targets breast cancer cells expressing higher levels of RNF126 by enhancing replication stress.

Original languageEnglish (US)
Pages (from-to)1629-1643
Number of pages15
JournalClinical Cancer Research
Volume24
Issue number7
DOIs
StatePublished - Apr 1 2018

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Yang, X., Pan, Y., Qiu, Z., Du, Z., Zhang, Y., Fa, P., Gorityala, S., Ma, S., Li, S., Chen, C., Wang, H., Xu, Y., Yan, C., Ruth, K., Ma, Z., & Zhang, J. (2018). Rnf126 as a biomarker of a poor prognosis in invasive breast cancer and chek1 inhibitor efficacy in breast cancer cells. Clinical Cancer Research, 24(7), 1629-1643. https://doi.org/10.1158/1078-0432.CCR-17-2242