Checkpoint Kinase 2 Inhibition Can Reverse Tamoxifen Resistance in ER-Positive Breast Cancer

Breast cancer is a heterogeneous disease. Tamoxifen is frequently used to treat ER-positive breast cancer. Our team has identified a novel splice variant of NCOR2, BQ323636.1 (BQ), that mediates tamoxifen resistance. However, the upstream factors that modulate BQ expression are not apparent. This st...

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Bibliographic Details
Published in:International journal of molecular sciences 2022-10, Vol.23 (20), p.12290
Main Authors: Tsoi, Ho, Tsang, Wai-Chung, Man, Ellen P. S., Leung, Man-Hong, You, Chan-Ping, Chan, Sum-Yin, Chan, Wing-Lok, Khoo, Ui-Soon
Format: Article
Language:English
Subjects:
Alternative splicing
Apoptosis
Ataxia
BQ323636.1
Breast cancer
CHK1 protein
CHK2
CHK2 protein
DNA damage
DNA microarrays
Gene expression
Health services
Kinases
Mortality
Phosphorylation
Resistance factors
siRNA
Tamoxifen
tamoxifen resistance
TMA
Ubiquitination
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Summary:Breast cancer is a heterogeneous disease. Tamoxifen is frequently used to treat ER-positive breast cancer. Our team has identified a novel splice variant of NCOR2, BQ323636.1 (BQ), that mediates tamoxifen resistance. However, the upstream factors that modulate BQ expression are not apparent. This study reveals that tamoxifen treatment causes induction of DNA damage which can enhance BQ expression. We show that DNA damage can activate the ATM/CHK2 and ATR/CHK1 signalling cascades and confirm that ATM/CHK2 signalling is responsible for enhancing the protein stability of BQ. siRNA or a small inhibitor targeting CHK2 resulted in the reduction in BQ expression through reduced phosphorylation and enhanced poly-ubiquitination of BQ. Inhibition of CHK2 by CCT241533 could reverse tamoxifen resistance in vitro and in vivo. Using clinical samples in the tissue microarray, we confirmed that high p-CHK2 expression was significantly associated with high nuclear BQ expression, tamoxifen resistance and poorer overall and disease-specific survival. In conclusion, tamoxifen treatment can enhance BQ expression in ER-positive breast cancer by activating the ATM/CHK2 axis. Targeting CHK2 is a promising approach to overcoming tamoxifen resistance in ER-positive breast cancer.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms232012290