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Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers.

ABSTRACT: RECQL1, a key member of the RecQ family of DNA helicases, is required for DNA replication and DNA repair. Two recent studies have shown that germline RECQL1 mutations are associated with increased breast cancer susceptibility. Whether altered RECQL1 expression has clinicopathologic significance in sporadic breast cancers is unknown. We evaluated RECQL1 at the transcriptomic level (METABRIC cohort, n = 1,977) and at the protein level [cohort 1, n = 897; cohort 2, n = 252; cohort 3 (BRCA germline deficient), n = 74]. In RECQL1-depleted breast cancer cells, we investigated anthracycline sensitivity. High RECQL1 mRNA was associated with intClust.3 (P = 0.026), which is characterized by low genomic instability. On the other hand, low RECQL1 mRNA was linked to intClust.8 [luminal A estrogen receptor-positive (ER+) subgroup; P = 0.0455] and intClust.9 (luminal B ER+ subgroup; P = 0.0346) molecular phenotypes. Low RECQL1 expression was associated with shorter breast cancer-specific survival (P = 0.001). At the protein level, low nuclear RECQL1 level was associated with larger tumor size, lymph node positivity, high tumor grade, high mitotic index, pleomorphism, dedifferentiation, ER negativity, and HER-2 overexpression (P < 0.05). In ER+ tumors that received endocrine therapy, low RECQL1 was associated with poor survival (P = 0.008). However, in ER- tumors that received anthracycline-based chemotherapy, high RECQL1 was associated with poor survival (P = 0.048). In RECQL1-depleted breast cancer cell lines, we confirmed doxorubicin sensitivity, which was associated with DNA double-strand breaks accumulation, S-phase cell-cycle arrest, and apoptosis. We conclude that RECQL1 has prognostic and predictive significance in breast cancers. Mol Cancer Ther; 16(1); 239-50. ©2016 AACR.

SUBMITTER: Arora A

PROVIDER: S-EPMC5222686 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers.

Arora Arvind A Parvathaneni Swetha S Aleskandarany Mohammed A MA Agarwal Devika D Ali Reem R Abdel-Fatah Tarek T Green Andrew R AR Ball Graham R GR Rakha Emad A EA Ellis Ian O IO Sharma Sudha S Madhusudan Srinivasan S

Molecular cancer therapeutics 20161111 1

RECQL1, a key member of the RecQ family of DNA helicases, is required for DNA replication and DNA repair. Two recent studies have shown that germline RECQL1 mutations are associated with increased breast cancer susceptibility. Whether altered RECQL1 expression has clinicopathologic significance in sporadic breast cancers is unknown. We evaluated RECQL1 at the transcriptomic level (METABRIC cohort, n = 1,977) and at the protein level [cohort 1, n = 897; cohort 2, n = 252; cohort 3 (BRCA germline ...[more]

PMID: 27837030

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Project description:Background: Silent information regulator 2 homolog 1 (SIRT1) is an evolutionarily conserved enzymes with nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase activity. SIRT1 is involved in a large variety of cellular processes, such as genomic stability, energy metabolism, senescence, gene transcription, and oxidative stress. SIRT1 has long been recognized as both a tumor promoter and tumor suppressor. Its prognostic role in cancers remains controversial. Methods: A meta-analysis of 13,138 subjects in 63 articles from PubMed, EMBASE, and Cochrane Library was performed to evaluate survival and clinicopathological significance of SIRT1 expression in various cancers. Results: The pooled results of meta-analysis showed that elevated expression of SIRT1 implies a poor overall survival (OS) of cancer patients [Hazard Ratio (HR) = 1.566, 95% CI: 1.293-1.895, P < 0.0001], disease free survival (DFS) (HR = 1.631, 95% CI: 1.250-2.130, P = 0.0003), event free survival (EFS) (HR = 2.534, 95% CI: 1.602-4.009, P = 0.0001), and progress-free survival (PFS) (HR = 3.325 95% CI: 2.762-4.003, P < 0.0001). Elevated SIRT1 level was associated with tumor stage [Relative Risk (RR) = 1.299, 95% CI: 1.114-1.514, P = 0.0008], lymph node metastasis (RR = 1.172, 95% CI: 1.010-1.360, P = 0.0363), and distant metastasis (RR = 1.562, 95% CI: 1.022-2.387, P = 0.0392). Meta-regression and subgroup analysis revealed that ethnic background has influence on the role of SIRT1 expression in predicting survival and clinicopathological characteristics of cancers. Overexpression of SIRT1 predicted a worse OS and higher TNM stage and lymphatic metastasis in Asian population especially in China. Conclusion: Our data suggested that elevated expression of SIRT1 predicted a poor OS, DFS, EFS, PFS, but not for recurrence-free survival (RFS) and cancer-specific survival (CCS). SIRT1 overexpression was associated with higher tumor stage, lymph node metastasis, and distant metastasis. SIRT1-mediated molecular events and biological processes could be an underlying mechanism for metastasis and SIRT1 is a therapeutic target for inhibiting metastasis, leading to good prognosis.

Dataset Information

Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers.

Publications

Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers.

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