DNA repair pathways in breast cancer: from mechanisms to clinical applications

Tufail, Muhammad

doi:10.1007/s10549-023-06995-z

Cited by 3 publications

(3 citation statements)

References 182 publications

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“…Prognostic biomarkers can indicate whether a patient is suitable for these treatments by considering mutations in BRCA1/BRCA2 in BCa which indicates a more aggressive phenotype. Identifying these mutations can inform clinicians that patients will be suitable for treatment with PARP inhibitors ( 294 ). Weil et al., show that dependent on the DNA repair pathway defects, breast and ovarian tumours can be more sensitive with platinum-based drugs or PARP inhibitors ( 295 ).…”

Section: The Tumour Microenvironment and Resistance To Therapymentioning

confidence: 99%

Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours

Bigos,

Quiles,

Lunj

et al. 2024

Front. Oncol.

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Hypoxia is a common feature of solid tumours affecting their biology and response to therapy. One of the main transcription factors activated by hypoxia is hypoxia-inducible factor (HIF), which regulates the expression of genes involved in various aspects of tumourigenesis including proliferative capacity, angiogenesis, immune evasion, metabolic reprogramming, extracellular matrix (ECM) remodelling, and cell migration. This can negatively impact patient outcomes by inducing therapeutic resistance. The importance of hypoxia is clearly demonstrated by continued research into finding clinically relevant hypoxia biomarkers, and hypoxia-targeting therapies. One of the problems is the lack of clinically applicable methods of hypoxia detection, and lack of standardisation. Additionally, a lot of the methods of detecting hypoxia do not take into consideration the complexity of the hypoxic tumour microenvironment (TME). Therefore, this needs further elucidation as approximately 50% of solid tumours are hypoxic. The ECM is important component of the hypoxic TME, and is developed by both cancer associated fibroblasts (CAFs) and tumour cells. However, it is important to distinguish the different roles to develop both biomarkers and novel compounds. Fibronectin (FN), collagen (COL) and hyaluronic acid (HA) are important components of the ECM that create ECM fibres. These fibres are crosslinked by specific enzymes including lysyl oxidase (LOX) which regulates the stiffness of tumours and induces fibrosis. This is partially regulated by HIFs. The review highlights the importance of understanding the role of matrix stiffness in different solid tumours as current data shows contradictory results on the impact on therapeutic resistance. The review also indicates that further research is needed into identifying different CAF subtypes and their exact roles; with some showing pro-tumorigenic capacity and others having anti-tumorigenic roles. This has made it difficult to fully elucidate the role of CAFs within the TME. However, it is clear that this is an important area of research that requires unravelling as current strategies to target CAFs have resulted in worsened prognosis. The role of immune cells within the tumour microenvironment is also discussed as hypoxia has been associated with modulating immune cells to create an anti-tumorigenic environment. Which has led to the development of immunotherapies including PD-L1. These hypoxia-induced changes can confer resistance to conventional therapies, such as chemotherapy, radiotherapy, and immunotherapy. This review summarizes the current knowledge on the impact of hypoxia on the TME and its implications for therapy resistance. It also discusses the potential of hypoxia biomarkers as prognostic and predictive indictors of treatment response, as well as the challenges and opportunities of targeting hypoxia in clinical trials.

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Section: The Tumour Microenvironment and Resistance To Therapymentioning

confidence: 99%

Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours

Bigos,

Quiles,

Lunj

et al. 2024

Front. Oncol.

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“…The latest progress in targeted therapy shows the prospect of using DNA repair pathway for BC therapy. Personalized therapy for specific DNA repair pathways based on genetic spectrum or tumor subtypes, such as DNA damage tolerance, homologous recombination (HR) repair, direct repair, translesion synthesis, non‐homologous end joining, nucleotide excision repair, base excision repair, mismatch repair and the Fanconi anemia pathway 9 . HR repair is a process in which sister chromatids are used as repair templates to accurately restore broken double‐stranded DNA 10 .…”

Section: Introductionmentioning

confidence: 99%

Homologous recombination deficiency reflects the heterogeneity and monitoring treatment response for patients with breast cancer

Long,

Wang,

2023

The Journal of Gene Medicine

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BackgroundIn breast cancer (BC), homologous recombination defect (HRD) is a common carcinogenic mechanism. It is meaningful to classify BC according to HRD biomarkers and to develop a platform for identifying BC molecular features, pathological features and therapeutic responses.MethodsIn total, 109 HRD genes were collected and screened by univariate Cox regression analysis to determine the prognostic genes, which were used to construct a consensus matrix to identify BC subtype. Differentially expressed genes (DEGs) were filtered by the Limma package and screened by random forest analysis to build a model to analyze the immunotherapy response and sensitivity and prognosis of patients suffering from BC to different drugs.ResultsThirteen out of 109 HRD genes were prognostic genes of BC, and BC was classified into two subgroups based on their expression. Cluster 1 had a significantly backward survival outcome and a significantly higher adaptive immunity score relative to cluster 2. Six genes were identified by random forest analysis as factors for developing the model. The model provided a prediction called risk score, which showed a significant stratification effect on BC prognosis, immunotherapy response and IC50 values of 62 drugs.ConclusionsIn the present study, two HRD subtypes of BC were successfully identified, for which mutation and immunological features were determined. A model based on differential genes of HRD subtypes was established, which was a potential predictor of prognosis, immunotherapy response and drug sensitivity of BC.

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“…Errors in the HR system can lead to cross-over and chromosomal substitutions with other non-homologous chromosomes. These exchanges result from a non-homologous repair (NHEJ and MMEJ) that can link breakpoints on different chromosomes [17]. Overall, tumor cells with a deficit of homologous recombination (HRD) accumulate larger imbalances due to migrating crossover structures of non-homologous chromosomes.…”

Section: Introductionmentioning

confidence: 99%

Assessing the Phenotype of a Homologous Recombination Deficiency Using High Resolution Array-Based Comparative Genome Hybridization in Ovarian Cancer

Magadeeva,

Qian,

Korff

et al. 2023

IJMS

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Ovarian cancer (OC) cells with homologous recombination deficiency (HRD) accumulate genomic scars (LST, TAI, and LOH) over a value of 42 in sum. PARP inhibitors can treat OC with HRD. The detection of HRD can be done directly by imaging these genomic scars, or indirectly by detecting mutations in the genes involved in HR. We show that HRD detection is also possible using high-resolution aCGH. A total of 30 OCs were analyzed retrospectively with high-resolution arrays as a test set and 19 OCs prospectively as a validation set. Mutation analysis was performed by HBOC TruRisk V2 panel to detect HR-relevant mutations. CNVs were clustered with respect to the involved HR genes versus the OC cases. In prospective validation, the HRD status determined by aCGH was compared with external HRD assessments. Two BRCA mutation carriers did not have HRD. OC could approximately differentiate into two groups with characteristic CNV patterns with different survival rates. Mutation frequencies have a linear regression on the HRD score. Mutations in individual HR-relevant genes do not always indicate HRD. This may depend on the mutation frequency in tumor cells. The aCGH shows the genomic scars of an HRD inexpensively and directly.

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DNA repair pathways in breast cancer: from mechanisms to clinical applications

Cited by 3 publications

References 182 publications

Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours

Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours

Homologous recombination deficiency reflects the heterogeneity and monitoring treatment response for patients with breast cancer

Assessing the Phenotype of a Homologous Recombination Deficiency Using High Resolution Array-Based Comparative Genome Hybridization in Ovarian Cancer

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