TY - JOUR
T1 - Rnf126 as a biomarker of a poor prognosis in invasive breast cancer and chek1 inhibitor efficacy in breast cancer cells
AU - Yang, Xiaosong
AU - Pan, You
AU - Qiu, Zhaojun
AU - Du, Zhanwen
AU - Zhang, Yao
AU - Fa, Pengyan
AU - Gorityala, Shashank
AU - Ma, Shanhuai
AU - Li, Shunqiang
AU - Chen, Ceshi
AU - Wang, Hongbing
AU - Xu, Yan
AU - Yan, Chunhong
AU - Ruth, Keri
AU - Ma, Zhefu
AU - Zhang, Junran
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85047878746&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-17-2242
DO - 10.1158/1078-0432.CCR-17-2242
M3 - Article
C2 - 29326282
AN - SCOPUS:85047878746
SN - 1078-0432
VL - 24
SP - 1629
EP - 1643
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -