Checkpoint Kinase 2 Inhibition Can Reverse Tamoxifen Resistance in ER-Positive Breast Cancer
| Autor: | Ho Tsoi, Wai-Chung Tsang, Ellen P. S. Man, Man-Hong Leung, Chan-Ping You, Sum-Yin Chan, Wing-Lok Chan, Ui-Soon Khoo |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Organic Chemistry
breast cancer BQ323636.1 CHK2 tamoxifen resistance DNA damage TMA CCT241533 CHK2 inhibitor Breast Neoplasms General Medicine Ataxia Telangiectasia Mutated Proteins Catalysis Computer Science Applications Inorganic Chemistry Checkpoint Kinase 2 Tamoxifen Cell Line Tumor Checkpoint Kinase 1 Humans Female Physical and Theoretical Chemistry RNA Small Interfering Phosphorylation Molecular Biology Spectroscopy DNA Damage |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 20; Pages: 12290 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms232012290 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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