Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers.
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.
Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.|Department of Oncology, Nottingham University Hospitals, Nottingham, United Kingdom.
Arvind
A
Arora
Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, Washington, DC.
Swetha
S
Parvathaneni
Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
Mohammed A
MA
Aleskandarany
School of Science and Technology, Nottingham Trent University, Clifton campus, Nottingham, United Kingdom.
Devika
D
Agarwal
Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
Reem
R
Ali
Department of Oncology, Nottingham University Hospitals, Nottingham, United Kingdom.
Tarek
T
Abdel-Fatah
Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
Andrew R
AR
Green
School of Science and Technology, Nottingham Trent University, Clifton campus, Nottingham, United Kingdom.
Graham R
GR
Ball
Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
Emad A
EA
Rakha
Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
Ian O
IO
Ellis
Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, Washington, DC. srinivasan.madhusudan@nottingham.ac.uk sudha.sharma@Howard.edu.
Sudha
S
Sharma
Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom. srinivasan.madhusudan@nottingham.ac.uk sudha.sharma@Howard.edu.|Department of Oncology, Nottingham University Hospitals, Nottingham, United Kingdom.
Srinivasan
S
Madhusudan
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D006801:Humans; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D047368:Tumor Burden
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D053484:RecQ Helicases