DNA repair in cancer initiation, progression, and therapy—a double-edged sword

Kiwerska, Katarzyna; Szyfter, Krzysztof

doi:10.1007/s13353-019-00516-9

Cited by 91 publications

(80 citation statements)

References 39 publications

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“…Indeed, a Cox hazard analysis of PanCan patient data revealed that high levels of DSB repair factors which constitute conserved targets of the FX-miRs, such as APLF, DCLRE1C, XRCC4, BRCA1, RAD51, CHEK1, and TOPBP1, correlate with worse cancer patient survival (Figure 4; Supplementary Table S5). This finding is in line with observations that the deregulation of DNA repair is associated with resistance to radiation therapy and cancer progression [68][69][70][71]. In summary, the positionally conserved Xq27.3-residing miRNA genes and their potential DSB repair pathway targets might play a crucial role for cancer progression and outcomes.…”

Section: Fraxa Is a Conserved Hotspot For Mirna Genes Inhibiting Compsupporting

confidence: 89%

MiRNAs Targeting Double Strand DNA Repair Pathways Lurk in Genomically Unstable Rare Fragile Sites and Determine Cancer Outcomes

Marquardt

Richter

Pützer

et al. 2020

Cancers

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Double strand break (DSB) repair mechanisms guard genome integrity and their deterioration causes genomic instability. Common and rare fragile sites (CFS and RFS, respectively) are particularly vulnerable to instability, and there is an inverse correlation between fragile site (FS) expression and DSB repair protein levels. Upon DSB repair dysfunction, genes residing at these sites are at greater risk of deregulation compared to genes located at non-FS. In this regard, it remains enigmatic why the incidence of miRNA genes at FS is higher compared to non-FS. Herein, using bioinformatics, we examined whether miRNA genes localized at FS inhibit components of DSB repair pathways and assessed their effects on cancer. We show that such miRNAs over-accumulate in RFS, and that FRAXA, which is expressed in Fragile X syndrome, is a conserved hotspot for miRNAs inhibiting DSB repair. Axes of FRAXA-residing miRNAs/DSB repair targets affect survival in a cancer type-specific manner. Moreover, copy number variations in the region encompassing these miRNA genes discriminate survival between male and female patients. Given that, thus far, only CFS have been considered relevant for carcinogenesis, our data are the first to associate RFS with cancer, through the impairment of DSB repair by the FRAXA-residing miRNAs.

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Section: Fraxa Is a Conserved Hotspot For Mirna Genes Inhibiting Compsupporting

confidence: 89%

MiRNAs Targeting Double Strand DNA Repair Pathways Lurk in Genomically Unstable Rare Fragile Sites and Determine Cancer Outcomes

Marquardt

Richter

Pützer

et al. 2020

Cancers

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“…Mismatch repair (MMR) pathway acts on nucleotide defects responsible for double strand mismatches. Double strand breaks are detected and repaired by two overlapping pathways, HR and Non-Homologous End-Joining (NHEJ) [23,24].…”

Section: Brca1 and Brca2 Germline Mutationsmentioning

confidence: 99%

The Landscape of Targeted Therapies in TNBC

Vagia

Mahalingam

Cristofanilli

2020

Cancers

278

198

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Triple negative breast cancer (TNBC) constitutes the most aggressive molecular subtype among breast tumors. Despite progress on the underlying tumor biology, clinical outcomes for TNBC unfortunately remain poor. The median overall survival for patients with metastatic TNBC is approximately eighteen months. Chemotherapy is the mainstay of treatment while there is a growing body of evidence that targeted therapies may be on the horizon with poly-ADP-ribose polymerase (PARP) and immune check-point inhibitors already established in the treatment paradigm of TNBC. A large number of novel therapeutic agents are being evaluated for their efficacy in TNBC. As novel therapeutics are now incorporated into clinical practice, it is clear that tumor heterogeneity and clonal evolution can result to de novo or acquired treatment resistance. As precision medicine and next generation sequencing is part of cancer diagnostics, tailored treatment approaches based on the expression of molecular markers are currently being implemented in clinical practice and clinical trial design. The scope of this review is to highlight the most relevant current knowledge regarding underlying molecular profile of TNBC and its potential application in clinical practice.

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“…A recent study showed that Epac could act synergistically with PDE4, an enzyme associated with the incidence of multiple tumors [71], in promoting rectal carcinoma [65]. Although the exact mechanism was not identified, the researchers found correlations between PDE4, Epac, cyclin E1, and the gap junction protein, connexin-43 (Cx43), in tissues obtained from patients diagnosed with invasive rectal carcinoma [65].…”

Section: Role Of Epac In Cancer Cell Proliferationmentioning

confidence: 99%

The Role of Epac in Cancer Progression

Wehbe

Slika

Mesmar

et al. 2020

IJMS

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Cancer continues to be a prime contributor to global mortality. Despite tremendous research efforts and major advances in cancer therapy, much remains to be learned about the underlying molecular mechanisms of this debilitating disease. A better understanding of the key signaling events driving the malignant phenotype of cancer cells may help identify new pharmaco-targets. Cyclic adenosine 3′,5′-monophosphate (cAMP) modulates a plethora of biological processes, including those that are characteristic of malignant cells. Over the years, most cAMP-mediated actions were attributed to the activity of its effector protein kinase A (PKA). However, studies have revealed an important role for the exchange protein activated by cAMP (Epac) as another effector mediating the actions of cAMP. In cancer, Epac appears to have a dual role in regulating cellular processes that are essential for carcinogenesis. In addition, the development of Epac modulators offered new routes to further explore the role of this cAMP effector and its downstream pathways in cancer. In this review, the potentials of Epac as an attractive target in the fight against cancer are depicted. Additionally, the role of Epac in cancer progression, namely its effect on cancer cell proliferation, migration/metastasis, and apoptosis, with the possible interaction of reactive oxygen species (ROS) in these phenomena, is discussed with emphasis on the underlying mechanisms and pathways.

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DNA repair in cancer initiation, progression, and therapy—a double-edged sword

Cited by 91 publications

References 39 publications

MiRNAs Targeting Double Strand DNA Repair Pathways Lurk in Genomically Unstable Rare Fragile Sites and Determine Cancer Outcomes

MiRNAs Targeting Double Strand DNA Repair Pathways Lurk in Genomically Unstable Rare Fragile Sites and Determine Cancer Outcomes

The Landscape of Targeted Therapies in TNBC

The Role of Epac in Cancer Progression

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