The E2F-Regulated Gene Chk1 Is Highly Expressed in Triple-Negative Estrogen Receptor−/Progesterone Receptor−/HER-2− Breast Carcinomas

Abstract

We previously showed that checkpoint kinase 1 (Chk1) and Claspin, two DNA-damage checkpoint proteins, were downregulated by 1,25-dihydroxyvitamin D 3 , a known inhibitor of cell proliferation. In the present study, we aimed to investigate the transcriptional regulation of Chk1 and Claspin and to study their expression levels in human breast cancer tissue. Transient transfection experiments in MCF-7 breast cancer cells showed that promoter activities of Chk1 and Claspin were regulated by the E2F family of transcription factors. Subsequently, transcript levels of Chk1, Claspin, and E2F1 were determined by quantitative reverse transcriptase-PCR analysis in 103 primary invasive breast carcinomas and were compared with several clinicopathologic variables in breast cancer. A strong correlation was found between Chk1 and Claspin transcript levels. Transcript levels of Chk1, Claspin, and E2F1 were highest in histologic grade 3 tumors and in tumors in which the expression of estrogen receptor (ER) and progesterone receptor (PR) was lost. Moreover, Chk1 expression was significantly elevated in grade 3 breast carcinomas showing a triple-negative ERÀ/PRÀ/HER-2À phenotype compared with other grade 3 tumors. Further research is warranted to validate the use of Chk1 inhibitors in triplenegative breast carcinomas for which treatment strategies are limited at present. [Cancer Res 2007;67(14):6574-81]

Inactivation of CHEK1 and EI24 is associated with the development of invasive cervical carcinoma: Clinical and prognostic implications

“…48 Differential nuclear and cytoplasmic localization of Chek1 was found in breast cancer tissues and cell lines. 49,50 Similar to us, breast tumors with deletion in CHEK1 showed reduced protein expression. 49 The transcript and protein expression of Chek1 also correlated with proliferation rate, tumor grade, type and size.…”

“…49 The transcript and protein expression of Chek1 also correlated with proliferation rate, tumor grade, type and size. 49,50 Variable level of Chek1 expressions has been reported in NHLs in accordance to the proliferating rate of the tumor. 30 But, some of the highly proliferating NHLs showed reduced expression of Chek1 concordant with low or normal RNA levels.…”

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

“…Replication stress or DNA damage is increased during o ncogenic transformation, which makes them more dependent upon DNA damage response pathways for cell survival (Bartkova et al, 2006;Bester et al, 2011;Vafa et al, 2002) . To cope with this stress many tumour cell lines elevate (Verlinden et al, 2007). In addition to Chk1, this study finds that some highly malignant bladder tumour cell lines also showed dependence upon ATM to protect them from apoptosis.…”

“…Since Chk1 kinase is over-expressed in many types of tumours (Verlinden et al, 2007), Chk1 seems to play a role to protect cancer cells from cell apoptosis in response to the treatment of anti-cancer drugs. Since tumour cells commonly lack G 1 checkpoint and rely on S and G 2 checkpoints instead, this incident suggests a potential of novel cancer therapeutics with the combination of Chk1 inhibitors and radiotherapy or clinical anti-cancer drugs.…”

Replication stress and cancer: It takes two to tango

“…On the contrary, ATR and Chk1 expression are frequently upregulated in cancer, in part because they are cell-cycle regulated genes and tumours have high proliferative indexes. Moreover, the expression of Chk1 is under the control of oncogenes such as Myc or E2F [76,77], which might be responsible for its enhanced levels in certain tumours. Why would tumours select for higher ATR and Chk1 levels?…”