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 - Funding Information:
Science Foundation of China grant (31571452 and 31271503) and Guangdong Provincial Natural Science Foundation of China grant (S2012010008368) and a startup fund from The First Affiliated Hospital of Sun Yat-sen University (to Z. Ma), and scholarships from the Chinese Scholarship Council (CSC). This research was also supported by the Radiation Resources Core Facility and Cytometry & Imaging Microscopy Core Facility of the Case Comprehensive Cancer Center (P30 CA43703).
Funding Information:
The work described was supported by a grant (R01CA154625) from the National Cancer Institute and seed grants from the Case Comprehensive Cancer Center and VeloSano Bike to Cure Foundation (to J. Zhang); a National Natural
Funding Information:
The authors apologize to colleagues whose work was not cited because of space limitations or ignorance. Our thanks for the service provided by BioMed Proofreading LLC. The work described was supported by a grant (R01CA154625) from the National Cancer Institute and seed grants from the Case Comprehensive Cancer Center and VeloSano Bike to Cure Foundation (to J. Zhang); a National Natural Science Foundation of China grant (31571452 and 31271503) and Guangdong Provincial Natural Science Foundation of China grant (S2012010008368) and a startup fund from The First Affiliated Hospital of Sun Yat-sen University (to Z. Ma), and scholarships from the Chinese Scholarship Council (CSC). This research was also supported by the Radiation Resources Core Facility and Cytometry & Imaging Microscopy Core Facility of the Case Comprehensive Cancer Center (P30 CA43703).
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 -