BRCA1 gene: function and deficiency

Takaoka, Miho; Miki, Yoshio

doi:10.1007/s10147-017-1182-2

Cited by 92 publications

(76 citation statements)

References 90 publications

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“…In the case of serous ovarian cancers, up to 25% of cases contain germline mutations with the most common being BRCA1 or BRCA2 mutations [2]. BRCA1/2 are multi-functioning tumor suppressor proteins that play a vital role in homologous recombination repair (HRR) of double-stranded DNA breaks (DSBs), cell cycle checkpoint activation, replication fork (RF) protection, and generating single-stranded DNA during repair after irradiation damage [3][4][5]. Defective HRR predisposes cancer cells to increased genomic instability and represents a unique vulnerability that can be exploited by anticancer therapy directed at complementary pathways.…”

Section: Introductionmentioning

confidence: 99%

Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells

et al. 2020

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Objective: Despite the promise of PARP inhibitors (PARPi) for treating BRCA1/2 mutated ovarian cancer (OC), drug resistance invariably develops. We hypothesized rationale drug combinations, targeting key molecules in DNA repair pathways and the cell cycle may be synergistic and overcome acquired PARPi resistance. Methods: Drug sensitivity to PARPi alone and in combination with inhibitors of key DNA repair and cell cycle proteins, including ATR (VE-821), Chk1 (MK-8776), Wee1 (MK-1775), RAD51 (RI-1) was assessed in PARPi-sensitive (UWB1) and -resistant (UWB1-R) gBRCA1 mutant OC cell lines using a cell proliferation assay. The Bliss synergy model was used to estimate the two-drug combination effect and pharmacologic synergy (Bliss score ≥ 0) or antagonistic (Bliss score ≥ 0) response of the PARPi in combination with the inhibitors. Results: IC50 for olaparib alone was 1.6 ± 0.9 µM compared to 3.4 ± 0.6 µM (p = 0.05) for UWB1 and UWB1-R cells, respectively. UWB1-R demonstrated increased sensitivity to ATRi (p = 0.04) compared to UWB1. Olaparib (0.3–1.25 µM) and ATRi (0.8–2.5 µM) were synergistic with Bliss scores of 17.2 ± 0.2, 11.9 ± 0.6 for UWB1 and UWB1-R cells, respectively. Olaparib (0.3–1.25 µM) and Chk1i(0.05–1.25 µM) were synergistic with Bliss scores of 8.3 ± 1.6, 5.7 ± 2.9 for UWB1 and UWB1-R cells, respectively. Conclusions: Combining an ATRi or Chk1i with olaparib is synergistic in both PARPi-sensitive and -resistant BRCA1 mutated OC cell models, and are rationale combinations for further clinical development.

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Section: Introductionmentioning

confidence: 99%

Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells

et al. 2020

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“…7 It includes cell cycle control, DNA repair, transcription and ubiquitination. 8,9 BRCA1 suppresses tumor growth in a PCa experimental model. 10 BRCA1-mutated or -deficient breast cancer cells seem to have more invasive phenotype including higher proliferation rate 11 and migration abilities.…”

Section: Introductionmentioning

confidence: 99%

Somatic aberrations of BRCA1 gene are associated with ALDH1, EGFR, and tumor progression in prostate cancer

Nastały

Stoupiec

et al. 2018

Intl Journal of Cancer

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BRCA1 is a pivotal tumor suppressor. Its dysfunction is known to play a role in different tumors. Among others, BRCA1 germline mutations account for higher risk and more aggressive course of prostate cancer (PCa). In addition, somatic BRCA1 gene loss was demonstrated to be a signature of PCa dissemination to lymph nodes and peripheral blood, and indicate worse clinical outcome. In order to substantiate the data for BRCA1 gene loss in PCa and reveal its phenotypical background, BRCA1 gene status was assessed in a large cohort of PCa patients and compared to different molecular factors. BRCA1 gene dosage was assessed in 2398 tumor samples from 1,199 PCa patients using fluorescent in situ hybridization. It was compared to clinico‐pathological parameters, patients’ outcome as well as selected proteins (Ki‐67, apoptosis marker, cytokeratins, vimentin, E‐ and N‐cadherin, ALDH1 and EGFR) examined immunohistochemically. BRCA1 losses were found in 10%, whereas gains appeared in 7% of 603 informative PCa patients. BRCA1 losses correlated to higher T stage (p = 0.027), Gleason score (p = 0.039), shorter time to biochemical recurrence in patients with Gleason score > 7 independently of other factors (multivariate analysis, p = 0.005) as well as expression of proteins regulating stemness and epithelial‐mesenchymal transition, that is, ALDH1 (p = 0.021) and EGFR (p = 0.011), respectively. BRCA1 gains correlated to shorter time to metastasis (p = 0.012) and expression of ALDH1 (p = 0.014). These results support the assumption that BRCA1 gene losses contribute to a progressive and stem cell‐like phenotype of PCa. Furthermore, they reveal that also BRCA1 gain conceivably representing loss‐of‐function might mark more invasive tumors.

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“…Although the 5′UTR‐20 G/A SNP was not associated with T2DM, the analysis in silico showed that the A allele produces a binding motif for the BRCA1 transcription factor. The BRCA1 tumor suppressor is a protein that has an important role in multiple biochemical and biological functions such as DNA repair, replication, cell cycle checkpoints, protein ubiquitination, transcriptional regulation, chromatin remodeling, and apoptosis (Takoaka & Miki, ). Recently, Kang et al () reported that BRCA1 regulates the expression of insulin‐like growth factor receptor‐1 (IGF‐IR) in human breast cancer cell line (MCF7).…”

Section: Discussionmentioning

confidence: 99%

The −44 C/G (rs1800972) polymorphism of the β‐defensin 1 is associated with increased risk of developing type 2 diabetes mellitus

Martínez-Ríos

Vargas‐Alarcón

Peña‐Duque

et al. 2018

Molec Gen & Gen Med

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Background The aim of this study was to establish the association of two polymorphisms of the β‐defensin 1 gene (DEFB1, OMIM#602056) with the risk of developing type 2 diabetes mellitus (T2DM) in a group of Mexican patients. Methods The 5′UTR −20 G/A, and −44 C/G polymorphisms of DEFB1 gene were genotyped by 5′ exonuclease TaqMan assays in a group of 252 patients with T2DM and 522 healthy control. Results Under dominant and additive models adjusted for the risk factors, the C allele of the −44 C/G polymorphism was associated with increased risk of T2DM (OR = 1.63, 95% CI = 1.07–2.48, pCdom = 0.021 and OR = 1.42, 95% CI = 1.05–1.91, pCadd = 0.023, respectively). In addition, the linkage disequilibrium analysis showed that AC haplotype was associated with an increased risk of developing T2DM (OR = 4.39, p = 0.04). The in‐silico analysis showed that the −44 C allele produces a binding site for the transcription factor Ikaros (IK). Conclusion This study demonstrates that the C allele of −44 C/G polymorphism, as well as haplotype AC are associated with the presence of T2DM in the Mexican population. The variation in this polymorphism of the DEFB1 gene could increase the migration of the macrophages to pancreatic islets accelerate the β‐cell dysfunction in T2DM.

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BRCA1 gene: function and deficiency

Cited by 92 publications

References 90 publications

Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells

Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells

Somatic aberrations of BRCA1 gene are associated with ALDH1, EGFR, and tumor progression in prostate cancer

The −44 C/G (rs1800972) polymorphism of the β‐defensin 1 is associated with increased risk of developing type 2 diabetes mellitus

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