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Many cancer-associated genes remain to be identified to clarify the underlying molecular mechanisms of cancer susceptibility and progression. Better understanding is also required of how mutations in cancer genes affect their products in the context of complex cellular networks. Here we have used a network modeling strategy to identify genes potentially associated with higher risk of breast cancer. Starting with four known genes encoding tumor suppressors of breast cancer, we combined gene expression profiling with functional genomic and proteomic (or 'omic') data from various species to generate a network containing 118 genes linked by 866 potential functional associations. This network shows higher connectivity than expected by chance, suggesting that its components function in biologically related pathways. One of the components of the network is HMMR , encoding a centrosome subunit, for which we demonstrate previously unknown functional associations with the breast cancer–associated gene BRCA1 . Two case-control studies of incident breast cancer indicate that the HMMR locus is associated with higher risk of breast cancer in humans. Our network modeling strategy should be useful for the discovery of additional cancer-associated genes.

The BRCA2 tumor suppressor protects genome integrity by promoting homologous recombination-based repair of DNA breaks, stability of stalled DNA replication forks and DNA damage-induced cell cycle checkpoints. BRCA2 deficient cells display the radio-resistant DNA synthesis (RDS) phenotype, however the mechanism has remained elusive. Here we show that cells without BRCA2 are unable to sufficiently restrain DNA replication fork progression after DNA damage, and the underrestrained fork progression is due primarily to Primase-Polymerase (PRIMPOL)-mediated repriming of DNA synthesis downstream of lesions, leaving behind single-stranded DNA gaps. Moreover, we find that BRCA2 associates with the essential DNA replication factor MCM10 and this association suppresses PRIMPOL-mediated repriming and ssDNA gap formation, while having no impact on the stability of stalled replication forks. Our findings establish an important function for BRCA2, provide insights into replication fork control during the DNA damage response, and may have implications in tumor suppression and therapy response. Tumor suppressor BRCA2 is known to stabilize and restart stalled DNA replication forks. Here the authors show that BRCA2 is recruited to the replication fork through its interaction with MCM10 and inhibits Primase-Polymerase-mediated repriming, lesion bypass and single strand DNA gap formation after DNA damage.

Poly (ADP-ribose) polymerase (PARP) inhibitors effectively kill tumours defective in the BRCA1 or BRCA2 genes through the concept of synthetic lethality. It is suggested that PARP inhibitors cause an increase in DNA single-strand breaks (SSBs), which are converted during replication to irreparable toxic DNA double-strand breaks (DSBs) in BRCA1/2 defective cells. There are a number of recent reports challenging this model. Here, alternative models that are not mutually exclusive are presented to explain the synthetic lethality between BRCA1/2 and PARP inhibitors. One such model proposes that PARP inhibition causes PARP-1 to be trapped onto DNA repair intermediates, especially during base excision repair. This may in turn cause obstruction to replication forks, which require BRCA-dependent homologous recombination to be resolved. In another model, PARP is directly involved in catalysing replication repair in a distinct pathway from homologous recombination. Experimental evidence supporting these novel models to explain the PARP-BRCA synthetic lethality are discussed. ► PARP-1 is not a base excision repair protein. ► SSBs do not accumulate as a primary lesion after PARP inhibition. ► PARP is hyperactivated in BRCA2 defective cells, reactivating stalled forks.

The CRISPR–Cas9 system provides a versatile toolkit for genome engineering that can introduce various DNA lesions at specific genomic locations. However, a better understanding of the nature of these lesions and the repair pathways engaged is critical to realizing the full potential of this technology. Here we characterize the different lesions arising from each Cas9 variant and the resulting repair pathway engagement. We demonstrate that the presence and polarity of the overhang structure is a critical determinant of double-strand break repair pathway choice. Similarly, single nicks deriving from different Cas9 variants differentially activate repair: D10A but not N863A-induced nicks are repaired by homologous recombination. Finally, we demonstrate that homologous recombination is required for repairing lesions using double-stranded, but not single-stranded DNA as a template. This detailed characterization of repair pathway choice in response to CRISPR–Cas9 enables a more deterministic approach for designing research and therapeutic genome engineering strategies. CRISPR-Cas9 has rapidly become a common molecular biology tool for modifying genomes and has been modified to generate single-strand nicks as well as double-strand breaks. Here the authors explore the DNA repair pathways activated by the different variants of Cas9.

Olaparib (Lynparza ™ ) is an oral, small molecule, poly (ADP-ribose) polymerase inhibitor being developed by AstraZeneca for the treatment of solid tumours. The primary indication that olaparib is being developed for is BRCA mutation-positive ovarian cancer. A capsule formulation of the drug has received approval for use in this setting in the EU and USA, and a tablet formulation is in global phase III trials (including in the USA, EU, Australia, Brazil, Canada, China, Israel, Japan, Russia and South Korea). In addition, phase III trials in breast, gastric and pancreatic cancer are underway/planned, and phase I/II investigation is being conducted in other malignancies, including prostate cancer, non-small cell lung cancer, Ewing’s sarcoma and advanced cancer. This article summarizes the milestones in the development of olaparib leading to this first approval for ovarian cancer.

In this study, a library of novel sulfonamide-based Schiff bases 3a - j was synthesized in high yield (75 to 89%). The FTIR, 1 H NMR, and 13 C NMR spectroscopic techniques and mass analysis were used to characterize the synthesized compounds. Their anticancer activity was assessed in vitro on the breast cancer (MCF-7) and healthy human breast epithelial (MCF-10 A) cell lines over 48 and 72 h using the MTT assay. Most of the synthesized compounds demonstrated promising activity, with compound 3i showing particularly high efficacy at 48 and 72 h (IC 50  = 4.85 ± 0.006 and 4.25 ± 0.009 µM) against the MCF-7 breast cancer cell line. Furthermore, molecular docking studies were performed for compounds 3a - j with the PDB: (3UV7) protein of the breast cancer susceptibility gene 2 (BRCA2). The obtained results revealed that compound 3i has the strongest binding affinity energy (-7.99 kcal/mol), consistent with the obtained experimental data. Additionally, molecular dynamics (MD) simulation assays confirm the formation of a stable 3i -BRCA2 complex with strong binding affinity through the formation of hydrogen bonds. Antioxidant activities were determined by in vitro assay DPPH cation radical activity method. Interestingly, the compound 3j (IC 50  = 12.36 ± 0.55 µM) had comparable activity with ascorbic acid (IC 50  = 13.58 ± 0.38 µM) in the antioxidant assay. The results of this research could potentially contribute to the development of new therapeutic agents useful in fighting caused by breast cancer.

Tumor diseases represent a significant global health challenge, impacting both humans and companion animals, notably dogs. The parallels observed in the pathophysiology of cancer between humans and dogs underscore the importance of advancing comparative oncology and translational research methodologies. Furthermore, dogs serve as valuable models for human cancer research due to shared environments, genetics, and treatment responses. In particular, breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2), which are critical in human cancer, also influence the development and progression of canine tumors. The role of BRCA1 and BRCA2 in canine cancers remains underexplored, but its potential significance as therapeutic targets is strongly considered. This systematic review aims to broaden the discussion of BRCA1 and BRCA2 beyond mammary tumors, exploring their implications in various canine cancers. By emphasizing the shared genetic underpinnings between species and advocating for a comparative approach, the review indicates the potential of BRCA genes as targets for innovative cancer therapies in dogs, contributing to advances in human and veterinary oncology.

It is well known that the activation of Aurora A/B (Aur A/B) or inactivation of BRCA1/2 induces tumor formation. Others and we have reported that the mutual suppression between Aur A/B and BRCA1/2 may manipulate cancer cell growth and tumorigenesis, however, the interactive regulation and mechanism between these molecules are still elusive. In this study, by consecutive silencing of Aur A/B or/and BRCA1/2 with specific shRNAs, we showed that, in BRCA2-deficient pancreatic cancer cell line Capan-1 and in ovarian cancer cell line OVCA433, Aur A/B and BRCA1/2 inversely regulated the expression of each other likely through proteasome-mediated proteolysis but not through gene transcription. Aur A/B and BRCA1/2 conversely regulated cell cycle progression mainly through control of p53 and cyclin A. Moreover, the disruption of Aur A/B blocked abnormal cytokinesis and decreased cell multinuclearity and chromosome tetraploidy, whereas the deprivation of BRCA1/2 promoted the abnormal cytokinesis and enhanced the cell multinuclearity and tetraploidy. Furthermore, we showed by animal assays that the depletion of Aur A/B inhibited tumor growth of both cell lines, while the knockdown of BRCA1/2 promoted the tumor growth. However, the concurrent silencing of Aur A/B and BRCA1/2 diminished the effects of these molecules on the regulation of cell cycle, cytokinesis, and tetraploidy, leading to the burdened tumor sizes similar to those induced by scrambled shRNA-treated control cells. In summary, our study revealed that the negative interplay between Aur A/B and BRCA1/2 inversely controls the cell proliferation, cell cycle progression, cell multinuclearity, and tetraploidization to modulate tumorigenesis.

In order to study the role of BRCA2 protein in homologous recombination repair and radio‐sensitization, we utilized RNA interference strategy in vitro and in vivo with human tumor cells. HeLa cells transfected with small‐interfering BRCA2 NA (BRCA2 siRNA) (Qiagen) as well as negative‐control siRNA for 48 h were irradiated, and several critical end points were examined. The radiation cell survival level was significantly reduced in HeLa cells with BRCA2 siRNA when compared with mock‐ or negative‐control siRNA transfected cells. DNA double strand break repair as measured by constant field gel‐electrophoresis showed a clear inhibition in cells with BRCA2 siRNA, while little inhibition was observed in cells with negative control siRNA. Our immuno‐staining experiments revealed a significant delay in Rad51 foci formation in cells with BRCA2 siRNA when compared with the control populations. However, none of the non‐homologous end joining proteins nor the phosphorylation of DNA‐dependent protein kinase catalytic subunit was affected in cells transfected with BRCA2 siRNA. In addition, the combined treatment with radiation and BRCA2 siRNA in xenograft model with HeLa cells showed an efficient inhibition of in vivo tumor growth. Our results demonstrate down‐regulation of BRCA2 leads to radio‐sensitization mainly through the inhibition of homologous recombination repair type double‐strand break repair; a possibility of using BRCA2 siRNA as an effective radiosensitizer in tumor radiotherapy may arise. (Cancer Sci 2008; 99: 810–815)

Background BRCA1 gene inactivation causes chromosomal instability, leading to rapid accumulation of chromosomal rearrangements and mutations. The loss of BRCA1 function due to either germline/somatic mutation or epigenetic silencing is observed in most high-grade serous carcinomas of the ovary. Methods DNA ploidy and gene expression profile were used in order to compare gross genomic alteration and gene expression pattern between cases with BRCA1 loss through mutation, BRCA1 epigenetic loss, and no BRCA1 loss in cases of high-grade serous carcinoma with known BRCA1 and BRCA 2 status. Results Using image cytometry and oligonucleotide microarrays, we analyzed DNA ploidy, S-phase fraction and gene expression profile of 28 consecutive cases of ovarian high-grade serous adenocarcinomas, which included 8 tumor samples with BRCA1 somatic or germline mutation, 9 samples with promoter hypermethylation of BRCA1, and 11 samples with no BRCA1 loss. None had BRCA2 mutations. The prevalence of aneuploidy and tetraploidy was not statistically different in the three groups with different BRCA1 status. The gene expression profiles were also very similar between the groups, with only two genes showing significant differential expression when comparison was made between the group with BRCA1 mutation and the group with no demonstrable BRCA1 loss. There were no genes showing significant differences in expression when the group with BRCA1 loss through epigenetic silencing was compared to either of the other two groups. Conclusions In this series of 28 high-grade serous carcinomas, gross genomic alteration characterized by aneuploidy did not correlate with BRCA1 status. In addition, the gene expression profiles of the tumors showed negligible differences between the three defined groups based on BRCA1 status. This suggests that all ovarian high-grade serous carcinomas arise through oncogenic mechanisms that result in chromosomal instability, irrespective of BRCA status; the molecular abnormalities underlying this in the BRCA intact tumors remains unknown.