BRCA1 and Metastasis: Outcome of Defective DNA Repair

Krishnan, R.; Patel, Parasvi S.; Hakem, Razqallah

doi:10.3390/cancers14010108

Cited by 14 publications

(4 citation statements)

References 101 publications

(145 reference statements)

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“…Regarding the stratification of risk factors according to the sites of metastasis, we found that a family history of breast or ovarian cancer was associated with higher rates of metastasis to multiple sites. Family history as a risk factor is mainly due to the association with BRCA1 mutations [ 57 ], which have been identified as contributors to the metastatic and aggressive nature of tumor cells [ 58 ]. Fasching et al [ 57 ] reported that brain metastasis was frequently seen in patients with BRCA1 mutations whereas Song et al [ 59 ] found that carriers of this mutation frequently experience lung and lymph node metastasis.…”

Section: Discussionmentioning

confidence: 99%

Survival according to the site of metastasis in triple-negative breast cancer patients: The Peruvian experience

Piedra-Delgado,

Chambergo-Michilot,

Morante

et al. 2024

PLoS ONE

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Background Evidence regarding differences in survival associated with the site of metastasis in triple-negative breast cancer (TNBC) remains limited. Our aim was to analyze the overall survival (OS), distant relapse free survival (DRFS), and survival since the diagnosis of the relapse (MS), according to the side of metastasis. Methods This was a retrospective study of TNBC patients with distant metastases at the Instituto Nacional de Enfermedades Neoplasicas (Lima, Peru) from 2000 to 2014. Prognostic factors were determined by multivariate Cox regression analysis. Results In total, 309 patients were included. Regarding the type of metastasis, visceral metastasis accounted for 41% and the lung was the most frequent first site of metastasis (33.3%). With a median follow-up of 10.2 years, the 5-year DRFS and OS were 10% and 26%, respectively. N staging (N2-N3 vs. N0, HR = 1.49, 95%CI: 1.04–2.14), metastasis in visceral sites (vs. bone; HR = 1.55, 95%CI: 0.94–2.56), the central nervous system (vs. bone; HR = 1.88, 95% CI: 1.10–3.22), and multiple sites (vs. bone; HR = 2.55, 95%CI:1.53–4.25) were prognostic factors of OS whereas multiple metastasis (HR = 2.30, 95% CI: 1.42–3.72) was a predictor of MS. In terms of DRFS, there were no differences according to metastasis type or solid organ. Conclusion TNBC patients with multiple metastasis and CNS metastasis have an increased risk of death compared to those with bone metastasis in terms of OS and MS.

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Section: Discussionmentioning

confidence: 99%

Survival according to the site of metastasis in triple-negative breast cancer patients: The Peruvian experience

Piedra-Delgado,

Chambergo-Michilot,

Morante

et al. 2024

PLoS ONE

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“…Given its role in maintaining genomic integrity, it is not surprising that mutations in the BRCA1 gene increase the risk of developing breast, ovarian, and other cancers ( 3 , 4 ). Additionally, patients suffering from BRCA1-defective cancers are likely to experience poor clinical outcomes due to relapse, metastasis, and the development of a new contralateral tumor in the years following diagnosis ( 5 , 6 ). Therefore, it is critical to identify mechanisms that underlie the viability of these tumors and pinpoint novel therapeutic targets that specifically eliminate tumors that arise from BRCA1 mutations.…”

Section: Introductionmentioning

confidence: 99%

Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers

Patel

Algouneh

Krishnan

et al. 2023

Nucleic Acids Research

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BRCA1 mutations are associated with increased breast and ovarian cancer risk. BRCA1-mutant tumors are high-grade, recurrent, and often become resistant to standard therapies. Herein, we performed a targeted CRISPR-Cas9 screen and identified MEPCE, a methylphosphate capping enzyme, as a synthetic lethal interactor of BRCA1. Mechanistically, we demonstrate that depletion of MEPCE in a BRCA1-deficient setting led to dysregulated RNA polymerase II (RNAPII) promoter-proximal pausing, R-loop accumulation, and replication stress, contributing to transcription-replication collisions. These collisions compromise genomic integrity resulting in loss of viability of BRCA1-deficient cells. We also extend these findings to another RNAPII-regulating factor, PAF1. This study identifies a new class of synthetic lethal partners of BRCA1 that exploit the RNAPII pausing regulation and highlight the untapped potential of transcription-replication collision-inducing factors as unique potential therapeutic targets for treating cancers associated with BRCA1 mutations.

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“…Approximately 55-72% of women carrying a harmful BRCA1 gene variant, and around 45-69% of those with a harmful BRCA2 gene variant are expected to develop breast cancer during their 70 to 80 years of life (11,12). Metastasis of breast cancer occurs more frequently in carriers of BRCA1 mutation, often manifesting as lung metastases and distant lymph node involvement (13). In fact, over 75% of female breast cancer patients with BRCA1 mutation exhibit a TNBC phenotype (14).…”

Section: Introductionmentioning

confidence: 99%

BRCA1 mutation promotes sprouting angiogenesis in inflammatory cancer-associated fibroblast of triple-negative breast cancer

Fang,

Lee,

Hwang

et al. 2023

Preprint

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Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with inferior outcomes owing to its low treatment response and high invasiveness. Based on abundant cancer-associated fibroblasts (CAFs) and frequent mutation of breast cancer-associated 1 (BRCA1) in TNBC, the characteristics of CAFs in TNBC patients with BRCA1 mutation compared to wild-type BRCA1 were investigated using single-cell analysis. Intriguingly, we observed a dominant presence of inflammatory CAFs (iCAFs) in BRCA1 mutation compared to the wild-type BRCA1 TNBC patients. iCAFs in patients with BRCA1 mutation exhibited strong signaling to endothelial cells (ECs) clusters, including chemokine (C-X-C motif) ligand 1 (CXCL) and vascular endothelial growth factor (VEGF). During CXCL signaling, the atypical chemokine receptor 1 (ACKR1) mainly interacts with CXCL family members in tumor endothelial cells (TECs). ACKR1-high TECs also showed high expression levels of angiogenesis related genes, such as ANGPT2, MMP1 and SELE, which might lead to EC migration. Furthermore, iCAFs showed VEGF signals for FLT1 and KDR in TECs, which showed high co-expression with tip cell marker genes, including ZEB1 and MAFF, involved in sprouting angiogenesis. Moreover, BRCA1 mutation patient with relatively abundant iCAFs and tip cell gene expression, exhibited a limited response to neoadjuvant chemotherapy, including cisplatin and bevacizumab. Importantly, our study observed the intricate link between iCAFs-mediated angiogenesis and chemoresistance in TNBC with BRCA1 mutation.

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BRCA1 and Metastasis: Outcome of Defective DNA Repair

Cited by 14 publications

References 101 publications

Survival according to the site of metastasis in triple-negative breast cancer patients: The Peruvian experience

Survival according to the site of metastasis in triple-negative breast cancer patients: The Peruvian experience

Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers

BRCA1 mutation promotes sprouting angiogenesis in inflammatory cancer-associated fibroblast of triple-negative breast cancer

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