BRCA1/2 Signaling and Homologous Recombination Deficiency in Breast and Ovarian Cancer

Royfman, Rachel; Whiteley, Emma; Noe, Olivia; Morand, Susan; Creeden, Justin; Stanbery, Laura; Hamouda, Danae; Nemunaitis, John

doi:10.2217/fon-2021-0072

Cited by 8 publications

(3 citation statements)

References 82 publications

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“…On the regulation of HRR, FOXM1 has been implicated in the activation of HRR. FOXM1 has been reported to upregulate BRIP1 [ 38 ] and NBS1 [ 39 ], and FOXM1 activation upregulates RAD51 and BRCA1 in idiopathic pulmonary fibroblasts to activate HRR [ 40 ], with FOXM1 being a transcription factor that plays an important role in proliferation, cell cycle control, DNA repair, tumorigenesis, cancer progression, and tumor growth [ 41 , 42 ]. FOXO3a is reported to transcriptionally regulate GADD45 to mediate DNA repair [ 30 ], and is known to suppress DNA double-strand-break-induced mutation [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

FOXO3a Mediates Homologous Recombination Repair (HRR) via Transcriptional Activation of MRE11, BRCA1, BRIP1, and RAD50

et al. 2022

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To test whether homologous recombination repair (HRR) depends on FOXO3a, a cellular aging model of human dermal fibroblast (HDF) and tet-on flag-h-FOXO3a transgenic mice were studied. HDF cells transfected with over-expression of wt-h-FOXO3a increased the protein levels of MRE11, BRCA1, BRIP1, and RAD50, while knock-down with siFOXO3a decreased them. The protein levels of MRE11, BRCA1, BRIP1, RAD50, and RAD51 decreased during cellular aging. Chromatin immunoprecipitation (ChIP) assay was performed on FOXO3a binding accessibility to FOXO consensus sites in human MRE11, BRCA1, BRIP1, and RAD50 promoters; the results showed FOXO3a binding decreased during cellular aging. When the tet-on flag-h-FOXO3a mice were administered doxycycline orally, the protein and mRNA levels of flag-h-FOXO3a, MRE11, BRCA1, BRIP1, and RAD50 increased in a doxycycline-dose-dependent manner. In vitro HRR assays were performed by transfection with an HR vector and I-SceI vector. The mRNA levels of the recombined GFP increased after doxycycline treatment in MEF but not in wt-MEF, and increased in young HDF comparing to old HDF, indicating that FOXO3a activates HRR. Overall, these results demonstrate that MRE11, BRCA1, BRIP1, and RAD50 are transcriptional target genes for FOXO3a, and HRR activity is increased via transcriptional activation of MRE11, BRCA1, BRIP1, and RAD50 by FOXO3a.

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Section: Discussionmentioning

confidence: 99%

FOXO3a Mediates Homologous Recombination Repair (HRR) via Transcriptional Activation of MRE11, BRCA1, BRIP1, and RAD50

et al. 2022

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“…Indeed, a dysregulation of factors related to R-loop resolution results in various types of DNA damage and genomic instability, which can trigger cancer progression [ 43 ]. BRCA1/2, which are major regulators of genome maintenance, are mutated in some cancers that show high levels of R-loops and altered oncogene expression, including breast cancer [ 42 , 44 , 45 , 46 ]. Moreover, since BRCA1/2 functions along with FA proteins in DNA integrity pathways, their deficiency results in the accumulation of DNA damage and R-loops due to interference between the FA-BRCA pathway.…”

Section: R-loop-mediated Dna Damage and Genomic Instabilitymentioning

confidence: 99%

Clinical and Mechanistic Implications of R-Loops in Human Leukemias

Lee

Miller

Kim

2023

IJMS

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Genetic mutations or environmental agents are major contributors to leukemia and are associated with genomic instability. R-loops are three-stranded nucleic acid structures consisting of an RNA–DNA hybrid and a non-template single-stranded DNA. These structures regulate various cellular processes, including transcription, replication, and DSB repair. However, unregulated R-loop formation can cause DNA damage and genomic instability, which are potential drivers of cancer including leukemia. In this review, we discuss the current understanding of aberrant R-loop formation and how it influences genomic instability and leukemia development. We also consider the possibility of R-loops as therapeutic targets for cancer treatment.

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“…Such cancers are frequently homologous recombination deficient (HRD) due to inactivating mutations in these genes, making them susceptible to PARP inhibitors (PARPis), a new kind of cancer treatment designed for such malignancies based on the idea of synthetic lethality [ 3 ]. Over the past couple of decades, several PARPis have been licensed to facilitate the therapy of appropriately chosen ovarian and breast cancer patients [ 2 , 4 ]. However, which patients are suitable for PARPi is still a clinical question worthy of investigation.…”

Section: Introductionmentioning

confidence: 99%

Somatic mutations in four novel genes contribute to homologous recombination deficiency in breast cancer: a real‐world clinical tumor sequencing study

Huang,

Qiu,

Ding

et al. 2024

The Journal of Pathology CR

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Breast cancers involving mutations in homologous recombination (HR) genes, most commonly BRCA1 and BRCA2 (BRCA1/2), respond well to PARP inhibitors and platinum‐based chemotherapy. However, except for these specific HR genes, it is not clear which other mutations contribute to homologous recombination defects (HRD). Here, we performed next‐generation sequencing of tumor tissues and matched blood samples from 119 breast cancer patients using the OncoScreen Plus panel. Genomic mutation characteristics and HRD scores were analyzed. In the HR genes, we found that BRCA1/2 and PLAB2 mutations were related to HRD. HRD was also detected in a subset of patients without germline or somatic mutations in BRCA1/2, PLAB2, or other HR‐related genes. Notably, LRP1B, NOTCH3, GATA2, and CARD11 (abbreviated as LNGC) mutations were associated with high HRD scores in breast cancer patients. Furthermore, functional experiments demonstrated that silencing CARD11 and GATA2 impairs HR repair efficiency and enhances the sensitivity of tumor cells to olaparib treatment. In summary, in the absence of mutations in the HR genes, the sensitivity of tumor cells to PARP inhibitors and platinum‐based chemotherapy may be enhanced in a subset of breast cancer patients with LNGC somatic mutations.

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BRCA1/2 Signaling and Homologous Recombination Deficiency in Breast and Ovarian Cancer

Cited by 8 publications

References 82 publications

FOXO3a Mediates Homologous Recombination Repair (HRR) via Transcriptional Activation of MRE11, BRCA1, BRIP1, and RAD50

FOXO3a Mediates Homologous Recombination Repair (HRR) via Transcriptional Activation of MRE11, BRCA1, BRIP1, and RAD50

Clinical and Mechanistic Implications of R-Loops in Human Leukemias

Somatic mutations in four novel genes contribute to homologous recombination deficiency in breast cancer: a real‐world clinical tumor sequencing study

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