scholarly journals BRCA1 promoter hypermethylation, 53BP1 protein expression and PARP-1 activity as biomarkers of DNA repair deficit in breast cancer

BMC Cancer ◽  
2013 ◽  
Vol 13 (1) ◽  
Author(s):  
William Jacot ◽  
Simon Thezenas ◽  
Romain Senal ◽  
Cathy Viglianti ◽  
Anne-Claire Laberenne ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Protein Expression ◽  
Promoter Hypermethylation ◽  
Brca1 Promoter ◽  
Parp 1

scholarly journals BRCA1 Promoter Hypermethylation is Associated with Good Prognosis and Chemosensitivity in Triple-Negative Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 828 ◽  
Author(s):  
William Jacot ◽  
Evelyne Lopez-Crapez ◽  
Caroline Mollevi ◽  
Florence Boissière-Michot ◽  
Joelle Simony-Lafontaine ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Protein Expression ◽  
Triple Negative ◽  
Surrogate Marker ◽  
Promoter Hypermethylation ◽  
Brca1 Protein ◽  
Brca1 Promoter ◽  
Basal Marker ◽  
N Stage

The aberrant hypermethylation of BRCA1 promoter CpG islands induces the decreased expression of BRCA1 (Breast Cancer 1) protein. It can be detected in sporadic breast cancer without BRCA1 pathogenic variants, particularly in triple-negative breast cancers (TNBC). We investigated BRCA1 hypermethylation status (by methylation-specific polymerase chain reaction (MS-PCR) and MassARRAY® assays), and BRCA1 protein expression using immunohistochemistry (IHC), and their clinicopathological significance in 248 chemotherapy-naïve TNBC samples. Fifty-five tumors (22%) exhibited BRCA1 promoter hypermethylation, with a high concordance rate between MS-PCR and MassARRAY® results. Promoter hypermethylation was associated with reduced IHC BRCA1 protein expression (p = 0.005), and expression of Programmed death-ligand 1 protein (PD-L1) by tumor and immune cells (p = 0.03 and 0.011, respectively). A trend was found between promoter hypermethylation and basal marker staining (p = 0.058), and between BRCA1 expression and a basal-like phenotype. In multivariate analysis, relapse-free survival was significantly associated with N stage, adjuvant chemotherapy, and histological subtype. Overall survival was significantly associated with T and N stage, histology, and adjuvant chemotherapy. In addition, patients with tumors harboring BRCA1 promoter hypermethylation derived the most benefit from adjuvant chemotherapy. In conclusion, BRCA1 promoter hypermethylation is associated with TNBC sensitivity to adjuvant chemotherapy, basal-like features and PD-L1 expression. BRCA1 IHC expression is not a good surrogate marker for promoter hypermethylation and is not independently associated with prognosis. Association between promoter hypermethylation and sensitivity to Poly(ADP-ribose) polymerase PARP inhibitors needs to be evaluated in a specific series of patients.

BRCA1 promoter hypermethylation and protein expression in ovarian carcinoma—an Indian study

Tumor Biology ◽  
2014 ◽  
Vol 35 (5) ◽  
pp. 4277-4284 ◽  
Author(s):  
V. Shilpa ◽  
Rahul Bhagat ◽  
C. S. Premalata ◽  
V. R. Pallavi ◽  
G. Ramesh ◽  
...  
Keyword(s):  
Protein Expression ◽  
Ovarian Carcinoma ◽  
Promoter Hypermethylation ◽  
Brca1 Promoter ◽  
Indian Study

scholarly journals Poly (ADP-ribose) Polymerase Promoter Hypermethylation Predispose Females to Breast Cancer

2019 ◽  
Vol 4 (1) ◽  
pp. 1-5
Author(s):  
Hussein Sabit ◽  
Shaimaa Nazir ◽  
Shimaa Abdel-Ghany ◽  
Osama A. Said ◽  
Eman W. Mohammed ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ductal Carcinoma ◽  
Lobular Carcinoma ◽  
Promoter Hypermethylation ◽  
Methylation Pattern ◽  
The Core ◽  
Specific Pcr ◽  
Tumor Tissues ◽  
Grade 3 ◽  
Parp 1

Being the most common cause of female deaths worldwide, breast cancer (BC) is intensively studied over the last two decades. In the present investigation, we evaluated the promoter methylation of three cancer-related genes; PARP-1, p21, and Rb in 10 bi-matched BC samples (ductal carcinoma and lobular carcinoma) included the core tumor and the adjacent normal tissue. H&E-stained histopathological sectioning revealed grade 2 and grade 3 tumor cells. Methylation-specific PCR (MSP) was performed using methylated (M) and unmethylated (U) primers for the three genes understudy. Histone acetyltransferase was measured in tumor and healthy tissues. A variation in the methylation state of the promoter region of the three genes were observed in core tumor and healthy tissue. PARP and Rb were hypermethylated in tumor tissues while p21 was partially methylated. HAT activities were positively correlated with the methylation pattern observed in healthy tissues, as HAT was highly expressed in healthy vs. tumor tissues. The obtained data might indicate that patients might be at risk of BC recurrence after being subjected to mastectomy. These data could be employed as a core in epigenetic-based data mining to establish a model for predicting the breast cancer-predisposed patients. However, further investigations are needed to fulfill this goal.

PARP inhibitors for anticancer therapy

2014 ◽  
Vol 42 (1) ◽  
pp. 82-88 ◽  
Author(s):  
Nicola Curtin
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Dna Repair ◽  
Anticancer Therapy ◽  
Parp Inhibitors ◽  
Cytotoxic Agents ◽  
Major Interest ◽  
Synthetically Lethal ◽  
Key Events ◽  
Parp 1

PARP-1 [poly(ADP-ribose) polymerase-1], which plays a key role in DNA repair, was discovered 50 years ago. PARPi (PARP inhibitors), originally made to probe the function of the enzyme, inhibit DNA repair and increase the potency of anticancer cytotoxic agents. PARPi of increasing potency were developed as chemo- and radio-sensitizers and first entered clinical trial in cancer patients in 2003. However, it was the revelation in 2005 that they were synthetically lethal in cells with DNA repair defects, found almost exclusively in some tumours, that led to a major interest in this class of drug. Several PARPi have entered clinical trials and show promising activity in breast, ovarian and other cancers associated with BRCA (breast cancer early-onset) mutations or other defects in homologous recombination DNA repair. It is likely that at least one of these will be licensed soon. The present review describes key events from the discovery to clinical application of PARPi.

scholarly journals Clinicopathological Significance of BRCA1 Promoter Hypermethylation in Thai Breast Cancer Patients

2015 ◽  
Vol 15 (24) ◽  
pp. 10585-10589 ◽  
Author(s):  
Pensri Saelee ◽  
Arkom Chaiwerawattana ◽  
Kumiko Ogawa ◽  
Young-Man Cho ◽  
Danai Tiwawech ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Promoter Hypermethylation ◽  
Breast Cancer Patients ◽  
Brca1 Promoter ◽  
Clinicopathological Significance

Treatment of Triple Negative Cell Lines with Olaparib to Block DNA Repair

2021 ◽  
Vol 21 ◽  
Author(s):  
Marina Gobbe Moschetta-Pinheiro ◽  
Jucimara Colombo ◽  
Murilo de Souza Tuckumantel ◽  
Gabriela Karam Rebolho ◽  
Debora Aparecida Pires de Campos Zuccari
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Repair ◽  
Cell Lines ◽  
Triple Negative ◽  
Parp Inhibitors ◽  
New Drugs ◽  
Control Group ◽  
Mammary Tumor Cells ◽  
Parp 1

Background: The most aggressive breast cancer is the triple negative histological type and the gold standard for its treatment is platinum salts, such as carboplatin. Due to high recurrence, there is a need to test new drugs, such as PARP inhibitors (PARPi) that induce lethality in cells with DNA damage. Olaparib is a PARPi, already used in some tumors, but not tested in canine species. Thus, the aim of this study was demonstrating the efficacy of olaparib in inhibiting DNA repair and controlling disease progression by decreasing the migration capacity of mammary tumor cells. Methods: The cell lines, CF41.Mg and MDA-MB-468, were cultured and was performed the MTT to define the best dose of carboplatin. Next, the cells were treated with 10 µM carboplatin, olaparib and with combination of both for 24 hours. PARP-1 protein and gene expression was evaluated by immunofluorescence, western blotting and qRT-PCR, respectively. The analysis of cell migration was performed in transwell chambers. Results: For CF41.Mg and MDA-MB-468 cell lines, there was decrease in PARP-1 protein and gene expression after treatment with carboplatin, olaparib and both in combination compared to the group without treatment (control) (p<0.05). Moreover, in both lines, reduction in invasion rate was observed after treatment with carboplatin, olaparib and when combined, compared to the control group (p<0.05). Conclusion: Our data suggests that carboplatin and olaparib were able to block DNA repair and control the cancer invasion, especially when used in combination. The results with olaparib in the canine line are unpublished. The olaparib should be a possible agent against human breast cancer and canine mammary tumors.

scholarly journals Identification of a Putative Tdp1 Inhibitor (CD00509) by in Vitro and Cell-Based Assays

2014 ◽  
Vol 19 (10) ◽  
pp. 1372-1382 ◽  
Author(s):  
Richard A. Dean ◽  
Hok Khim Fam ◽  
Jianghong An ◽  
Kunho Choi ◽  
Yoko Shimizu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Topoisomerase I ◽  
Mammary Epithelial Cells ◽  
Cancer Cell Line ◽  
Synthetic Lethal ◽  
Chemical Screening ◽  
Parp 1 ◽  
Mcf 7

Mutations of DNA repair pathways contribute to tumorigenesis and provide a therapeutic target for synthetic lethal interactions in tumor cells. Given that tyrosyl-DNA phosphodiesterase 1 (Tdp1) repairs stalled topoisomerase-I DNA complexes, we hypothesized that inhibition of Tdp1 has synthetic lethal effects in some cancers. To test this, we screened tumor arrays for Tdp1 expression and observed that Tdp1 is expressed in many tumors, including more than 90% of human breast tumors. Subsequent chemical screening identified putative Tdp1 inhibitors. Treatment of control human mammary epithelial cells and the breast cancer cell line MCF-7 with compound CD00509 preferentially sensitized MCF-7 cells to camptothecin and decreased cell proliferation 25% more than camptothecin treatment alone. This suggests that CD00509 specifically targeted Tdp1 in vitro, and CD00509 increased the sensitivity of wild-type murine embryonic fibroblasts (MEFs) to camptothecin to a degree comparable to that of Tdp1−/− MEFs. In addition, consistent with poly ADP-ribose polymerase-1 (PARP-1) collaborating with Tdp1 in DNA repair, combined Tdp1 and PARP-1 inhibition was more detrimental to MCF-7 cells than either treatment alone, whereas the combination was not additively harmful to control mammary cells. We conclude that targeting Tdp1 in anticancer therapy preferentially enhances the sensitivity of some breast cancer cells to camptothecin and may be an effective adjuvant for breast cancer therapy.

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