Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers

Arora, Arvind; Parvathaneni, Swetha; Aleskandarany, Mohammed A.; Agarwal, Devika; Ali, Reem; Abdel-Fatah, Tarek M.A.; Green, Andrew; Rakha, Emad A.; Ellis, Ian O.; Sharma, Sudha; Madhusudan, Srinivasan

doi:10.1158/1535-7163.mct-16-0290

Cited by 17 publications

(32 citation statements)

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“…Overall, increased accumulation and transactivation of p53, and increased double strand breaks are consistent with the observed sensitivity of RECQ1-deficienct cells to MMS as shown here and doxorubicin as recently reported [ 47 ].…”

Section: Resultssupporting

confidence: 92%

“…Analysis of TCGA data shows significant association of RECQ1 alterations with p53 mutation ( p < 0.001). Similarly, RECQ1 alterations exhibit significant tendency to co-occur with p53 mutations in METABRIC cohort of breast cancer patients where RECQ1 expression is correlated with patient survival [ 47 ]. To investigate whether RECQ1 mRNA expression predicts response to chemotherapy, we explored a large gene expression data set of 3951 human breast tumors ( http://kmplot.com/analysis/index.php?p=service&default=true ) [ 55 ].…”

Section: Resultsmentioning

confidence: 99%

“…In oral squamous cell carcinoma, RECQ1 expression correlated with cisplatin resistance [ 59 ] and RECQ1-depletion significantly augmented the in vivo anticancer effects of the drug cis-platinum (II) diammine dichloride that induce inter-strand cross links in DNA to impair progression of replication forks [ 19 ]. In sporadic ER- negative breast tumors, high RECQ1 expression is associated with poor survival in patients that received anthracycline based chemotherapy; and RECQ1-depletion in breast cancer cells increased doxorubicin chemosensitivity owing to DNA double strand breaks accumulation, S-phase cell cycle arrest and apoptosis [ 47 ]. Viziteu et al recently reported that RecQ helicases are deregulated in hematological malignancies compared to their normal counterparts and expression of RECQ1 was associated with significantly poor survival [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

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RECQ1 expression is upregulated in response to DNA damage and in a p53-dependent manner

Parvathaneni

Chaudhary

et al. 2017

Oncotarget

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Sensitivity of cancer cells to DNA damaging chemotherapeutics is determined by DNA repair processes. Consequently, cancer cells may upregulate the expression of certain DNA repair genes as a mechanism to promote chemoresistance. Here, we report that RECQ1, a breast cancer susceptibility gene that encodes the most abundant RecQ helicase in humans, is a p53-regulated gene, potentially acting as a defense against DNA damaging agents. We show that RECQ1 mRNA and protein levels are upregulated upon treatment of cancer cells with a variety of DNA damaging agents including the DNA-alkylating agent methylmethanesulfonate (MMS). The MMS-induced upregulation of RECQ1 expression is p53-dependent as it was observed in p53-proficient but not in isogenic p53-deficient cells. The RECQ1 promoter is bound by endogenous p53 and is responsive to p53 in luciferase reporter assays suggesting that RECQ1 is a direct target of p53. Treatment with the chemotherapeutic drugs temozolomide and fotemustine also increased RECQ1 mRNA levels whereas depletion of RECQ1 enhanced cellular sensitivity to these agents. These results identify a previously unrecognized p53-mediated upregulation of RECQ1 expression in response to DNA damage and implicate RECQ1 in the repair of DNA lesions including those induced by alkylating and other chemotherapeutic agents.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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RECQ1 expression is upregulated in response to DNA damage and in a p53-dependent manner

Parvathaneni

Chaudhary

et al. 2017

Oncotarget

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“…Using these optimised IHC conditions, we proceeded to investigate CDK18 protein expression in the Nottingham Tenovus series of 1650 breast cancers for which detailed clinicopathological parameters and various molecular markers have been previously defined [ 18 – 21 ]. Similar to the commercial breast cancer TMAs, we observed nuclear as well as cytoplasmic staining of CDK18, however, nuclear expression was rare and cytoplasmic expression was more common within these samples (Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

The relationship of CDK18 expression in breast cancer to clinicopathological parameters and therapeutic response

et al. 2018

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BackgroundCyclin-Dependent Kinases (CDKs) are established anti-cancer drug targets and a new generation of CDK inhibitors are providing clinical benefits to a sub-set of breast cancer patients. We have recently shown that human CDK18 promotes efficient cellular responses to replication stress. In the current study, we have investigated the clinicopathological and functional significance of CDK18 expression levels in breast cancers.ResultsHigh CDK18 protein expression was associated with a triple negative and basal-like phenotype (p = 0.021 and 0.027 respectively) as well as improved patient survival, which was particularly significant in ER negative breast cancers (n = 594, Log Rank 6.724, p = 0.01) and those treated with chemotherapy (n = 270, Log Rank 4.575, p = 0.03). In agreement with these clinical findings, breast cancer cells genetically manipulated using a dCRISPR approach to express high levels of endogenous CDK18 exhibited an increased sensitivity to replication stress-inducing chemotherapeutic agents, as a consequence to defective replication stress signalling at the molecular level.ConclusionsThese data reveal that CDK18 protein levels may predict breast cancer disease progression and response to chemotherapy, and provide further rationale for potential targeting of CDK18 as part of novel anti-cancer strategies for human cancers.Materials and MethodsCDK18 protein expression was evaluated in 1650 breast cancers and correlated to clinicopathological parameters and survival outcomes. Similar analyses were carried out for genetic and transcriptomic changes in CDK18 within several publically available breast cancer cohorts. Additionally, we used a deactivated CRISPR/Cas9 approach (dCRISPR) to elucidate the molecular consequences of heightened endogenous CDK18 expression within breast cancer cells.

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“…About prognostic studies, there was only one study evaluating the correlation of RECQL expression and survival in breast cancer from England population. Aroraet et al reported that the low level of RECQL expression was associated with poorer survival than did those with high level expression [ 27 ]. By extending their findings, we could demonstrate that RECQL expression was strongly associated with worse DRFS and DSS in Chinese women with breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Low expression of RECQL is associated with poor prognosis in Chinese breast cancer patients

Ouyang

et al. 2018

BMC Cancer

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BackgroundRECQL is a number of the RecQ DNA helicase family and plays an important role in maintaining genome stability. Although several studies have reported that RECQL mutations were correlated with the susceptibility to breast cancer, the effect on prognosis in breast cancer was not yet clarified. Here, we explored the association between RECQL expression level and survival in patients with breast cancer.MethodsIn the first cohort, the RECQL mRNA expression level was evaluated in 774 primary breast cancer patients using a quantitative real-time PCR assay. Then, in the second independent cohort, the level of RECQL protein expression was detected in 322 patients with breast cancer using immunohistochemistry assay. Survival curves of patients with RECQL expression were compared using the Kaplan-Meier method with log-rank test.ResultsIn the first cohort of 774 breast cancer patients, the low expression level of RECQL mRNA was significantly correlated with aggressive clinicopathological characteristics, including the positive lymph node status (P = 0.026), HER2 overexpression (P < 0.001), ER negative status (P = 0.047) and high tumor grade (P = 0.041). Moreover, the low expression level of RECQL mRNA was significantly associated with poor distant recurrence-free survival (DRFS, unadjusted hazard ratio (HR): 2.77, 95% confidence interval (CI): 1.88–4.09, P < 0.001) and disease-specific survival (DSS, unadjusted HR: 3.10, 95% CI: 1.84–5.20,P < 0.001), and it remained an independent unfavorable factor for DRFS and DSS (DRFS: adjusted HR: 3.04, 95% CI: 1.89–4.87, P < 0.001; DSS: adjusted HR: 4.25, 95% CI: 2.12–8.46, P < 0.001). In the second cohort of 322 breast cancer patients, low expression of RECQL protein was also subject to poor survival in breast cancer, and it was an independent prognosis factor of poor DRFS by multivariate analysis (DRFS: adjusted HR: 2.12, 95% CI: 1.16–3.88, P = 0.015).ConclusionsBreast cancer patients with low RECQL expression had a worse survival. The expression level of RECQL may be a potential prognosis factor for breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4585-1) contains supplementary material, which is available to authorized users.

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Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers

Cited by 17 publications

References 42 publications

RECQ1 expression is upregulated in response to DNA damage and in a p53-dependent manner

RECQ1 expression is upregulated in response to DNA damage and in a p53-dependent manner

The relationship of CDK18 expression in breast cancer to clinicopathological parameters and therapeutic response

Low expression of RECQL is associated with poor prognosis in Chinese breast cancer patients

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