From mutation to treatment: The dual role of BRCA1 and BRCA2 in gynecological malignancy development and management a systematic review.

Both the p53 and BRCA genes (BRCA1 and BRCA2) are essential tumor suppressors that act as key guardians of genomic stability [ 33 ]. While both are crucial for preventing cancer, they function through different mechanisms. The BRCA genes primarily function in homologous recombination, a high-fidelity DNA repair process that repairs double-strand breaks. In contrast, p53 regulates the cell cycle, apoptosis (programmed cell death), and DNA repair through transcriptional control. Although their mechanisms differ, they share a common goal: preventing uncontrolled cell growth and the accumulation of genetic errors that lead to cancer. Disruption of either pathway through gene mutations significantly increases cancer susceptibility, highlighting their vital, albeit distinct, roles in maintaining cellular health [ 34 ].

BRCA1 and BRCA2 mutations play a crucial role in cancer development by disrupting the cell cycle and the homologous recombination DNA repair pathway [ 38 ]. These tumor suppressor genes work with proteins such as Rad51 to detect and repair DNA double-strand breaks (DSBs). Specifically, BRCA1 regulates the Mre11 single-strand nuclease to prepare DNA at break sites, while BRCA2 guides Rad51 to the damaged regions to form a repair complex. The transition between active and inert states of these complexes is regulated by post-translational modifications, such as protein phosphorylation [ 39 ]. Both BRCA1 and BRCA2 are essential for cell cycle checkpoints, preventing cells with damaged DNA from replicating. BRCA1's deletion, in particular, can cause growth retardation, increased apoptosis, aberrant centrosome duplication, and errors in the G2/M cell cycle checkpoint, leading to genomic instability [ 40 , 41 ]. This is supported by the finding that BRCA1 influences the expression, phosphorylation, and cellular localization of checkpoint kinase 1 (Chk1), a key component of the DNA damage response (DDR) cascade [ 42 ]. The genomic instability caused by BRCA1 depletion leads to mutations in additional genes, resulting in the upregulation of oncogenes like Cyclin D1, the proto-oncogene bHLH transcription factor (c-Myc), and Erb-B2 receptor tyrosine kinase 2 (ErbB2), while also causing a loss of heterozygosity in several tumor suppressor genes [ 27 ]. Interestingly, fewer than 25% of tumors with BRCA1 mutations harbor ErbB2 [ 43 ]. Furthermore, the interaction between full-length BRCA1 and p53 is significant, leading to p21 overexpression and triggering G1/S cell cycle arrest. Thus, disruption of the p53/p21-mediated cell cycle checkpoint by a BRCA1 mutation can ultimately lead to uncontrolled cell growth [ 44 ]. Mutations in BRCA1 and BRCA2 are therefore primarily responsible for genomic instability, leading to oncogene overexpression and a loss of cell cycle control, which are the main drivers of cancer development [ 45 ]. Rad51 activity needs to be tightly regulated, as hyperactivation may induce aberrant recombination events, leading to chromosomal translocations and genomic instability, whereas functional impairment results in defective homologous recombination repair and increased cellular sensitivity to DNA‐damaging agents. Two classes of positive regulators may primarily regulate the activity of Rad51: (i) BRCA2 and PALB2, which facilitate Rad51 recruitment and loading at DNA damage sites, and (ii) ATM and ATR kinases, which enhance Rad51 activity through specific phosphorylation events [ 46 ]. BRCA2 specifically binds the ATPase domain of Rad51. In addition, BRCA2 forms a complex with DSS1 (a small chaperone protein), preventing its own aggregation and enhancing the interaction with Rad51 [ 47 ]. PALB2 serves as a critical bridge between BRCA2 and Rad51. The N‐terminal chromo‐like domain of PALB2 binds directly to BRCA1, initiating the DNA damage response, whereas its C‐terminal WD40 domain interacts with BRCA2, facilitating BRCA2‐dependent recruitment of Rad51 to DNA damage sites [ 48 ]. When PALB2 is absent, this can lead to a 70%–80% reduction in Rad51 recruitment at the DSB. However, some PALB2 mutations (e.g., p.L35P) disrupt interaction with Rad51 without affecting binding to BRCA2, leading to selective HR defects [ 49 ]. Secondly, the DNA damage response kinases ATM/ATR dynamically regulate Rad51's functional state through site‐specific phosphorylation. For example, ATR can directly phosphorylate the Thr site of Rad51. This modification not only enhances the affinity of Rad51 for single‐stranded DNA but also promotes the filamentous assembly of its nuclear site and damage site. Meanwhile, ATM regulates the stability of the BRCA2‐PALB2‐Rad51 complex by phosphorylating the Ser site of BRCA2, thereby coordinating the precise recruitment and unloading of Rad51 at DSBs [ 50 ]. This differentiated post‐translational modification complements the BRCA2‐mediated loading mechanism, jointly ensuring that Rad51 can complete DNA repair at the correct time, location, and appropriate activity level. However, these two types of regulatory systems do not operate independently. For instance, Guo et al. found that ATM and ATR can synergistically enhance Rad51 repair efficiency by mediating PALB2 phosphorylation. The existence of this multidimensional regulatory network not only ensures high-fidelity HR repair but also effectively prevents the risk of abnormal genomic recombination caused by excessive Rad51 activation [ 51 ].

Poly (ADP-ribose) (PAR) is produced by PARPs from NAD, with nicotinamide as the end product. Poly (ADP-ribose) polymerase 1 (PARP1), the primary generator of cellular PAR, is activated by DNA damage. The mechanism of catalytic activation of PARP1 involves several steps, including binding of NAD to the catalytic pocket, unfolding of the helical domain (HD), binding to DNA via N-terminal zinc fingers (ZnF), and PAR catalysis [ 59 ]. Given PARP1's critical role in DNA repair, its inhibition has become a central concept in exploiting synthetic lethality is the simultaneous modification of two proteins or genes, say A and B, that results in the death of the cell. This idea is used in cancer treatment: gene A can represent an oncogenic process/pathway, an oncogene, or a tumor suppressor gene. Once identified, gene B becomes a potential therapeutic target for targeting dysfunctional cancer cells in A [ 60 ]. The (PARP1) catalytic cycle is illustrated by model A: PARP1 exists in a disordered state, often described as “beads on a string,” in its non-DNA-bound state. Three zinc finger-related domains, which are ZnF 1, 2, and 3, the BRCA1 C-terminus domain (BRCT), the tryptophan-, glycemic-, arginine-rich domain (WGR), the catalytic domain including a helical domain (HD), and an ADP-ribose transferase (ART) catalytic domain, comprise the domain structure. Damage to the DNA double helix sometimes leads to the production of single-strand breaks (SSBs), which offer PARP1 ZnF domains a binding site. The recruitment of DNA repair effectors, chromatin remodeling, and, ultimately, DNA repair are mediated by ART catalytic activity, which causes PARylation of PARP1 substrate proteins [ 61 ]. Failure of any component of PARP inhibitors will result in tumor development. Clinical PARP inhibitors, such as talazoparib and veliparib, exhibit varying cytotoxic activity. Trapped PARP1 on DNA hinders replication forks, producing DNA damage. The best DNA repair mechanism is homologous Recombination Repair (HRR), which involves the tumor suppressor proteins BRCA1 and BRCA2. Insufficient HRR can result in extensive genomic rearrangements, leading to synthetic lethality and the death of malignant cells [ 62 ].

The BRCA1 and BRCA2 genes are like the body's genetic safety guards. Their primary function is to repair DNA damage in our cells. However, sometimes, for various reasons, changes, or “mutations,” occur in these genes, rendering them unable to perform their roles. Genetic mutations in BRCA1 and BRCA2, whether inherited or acquired, disrupt the production of proteins that help protect the body from cancer. These mutations often occur at splice sites within genes, leading to premature termination of protein synthesis or the production of nonfunctional proteins. Processes such as promoter methylation can also affect gene function. These modifications impair the ability of these genes to perform their normal function of repairing DNA and protecting cells from cancer [ 65 , 68 ]. Mutations in the BRCA1 and BRCA2 genes lead to genomic instability, including chromosomal abnormalities and imbalances in gene copy number, which accelerate the growth of cancerous tumors [ 66 ]. The relative prevalence of BRCA1 and BRCA2 mutations varies by population. In a large commercial testing cohort comprising 46,276 individuals, pathogenic mutations were identified in 5795 cases, with 58% occurring in BRCA1 and 42% in BRCA2; conversely, other cohorts have reported an inverse distribution [ 69 ]. Mutations in BRCA1 and BRCA2 are strongly linked to hereditary breast and ovarian cancers, while reduced BRCA1 expression is also observed in a considerable proportion of sporadic cases. Breast cancer (BC) is one of the most prevalent malignancies in women. Every year, around 2.3 million women are diagnosed with breast cancer. It ranks as the fifth most significant cause of cancer-related mortality worldwide, accounting for 685,000 fatalities [ 70 ]. Numerous factors influence this cancer, including our environment, lifestyle (such as nutrition, exercise, and smoking), hormonal changes, and genetics. The chance of getting breast cancer is increased if there is a family history of the disease, as it may be hereditary [ 71 ]. About 5–10% of breast cancers are hereditary, mainly due to BRCA1/2 mutations, which markedly increase lifetime risk and often lead to earlier onset (<45 years) [ 72 ]. Although most cases are diagnosed after the age of 50, in the US, about 9–10% of cases occur in women younger than 45 years. These early-onset cases are more likely to be hereditary, most linked to pathogenic germline variants in the BRCA1 and BRCA2 genes [ 72 , 73 ]. The BRCA1 gene is the first gene linked to hereditary breast cancer [ 74 ]. Women with any mutation in BRCA1 or BRCA2 have a lifetime risk of developing BC of 45% to 80% [ 67 ]. Molecular profiling divides BC into intrinsic subtypes with distinct behavior and treatment responses: Luminal A, Luminal B, HER2-enriched, and Basal-like (which often overlaps with triple-negative disease); a “normal-like” group is sometimes reported, and a claudin-low phenotype has been described in some cohorts [ 75 ]. Women who have mutations in the BRCA1 gene are far more likely to acquire breast cancer, and this gene mutation also increases the risk of prostate cancer in men and ovarian cancer in women. As for the BRCA2 gene, about 35% of families that have women's early onset breast cancer show mutations in this gene, which also increases the risk of women's breast and ovarian cancer [ 76 ]. BC, linked to mutations in the BRCA1 gene, is characterized by very high cancer cell activity (rapid division) and greater infiltration of cancer cells into lymphatic vessels. This makes this type more aggressive [ 77 ]. This type of breast cancer often lacks hormone receptors such as estrogen (ER), progesterone (PR), and HER2/neu, making conventional treatment difficult. Additionally, the risk of P53 gene mutations is increased. Deletion of the BRCA1 gene, whether accompanied by a defect in the P53 gene or not, leads to a high prevalence of the TNBC, which is considered one of the most dangerous types [ 78 ]. In contrast, Tumors associated with the BRCA2 gene are often estrogen receptor (ER) positive and p53 gene mutation negative. Tumors in which the BRCA1 gene is normally functioning are often associated with the “luminal” type. A higher survival rate, slower progression, and a good response to hormonal therapy characterize this type. This makes treatment and management easier compared to other types [ 67 ]. Recent studies indicate that TNBC associated with BRCA1 mutations does not originate in basal stem cells, as previously thought, but rather in precursor cells called luminal progenitor cells. When the BRCA1 and p53 pathways become defective, this leads to abnormal changes in breast tissue formation, potentially leading to cancer [ 68 ]. Carriers of a BRCA1 mutation have a lifetime risk of breast cancer of up to 70%, compared to around 12% for non-carriers [ 79 ]. Clinics and hospitals now perform screening for the BRCA1 and BRCA2 genes, particularly for individuals with a breast cancer diagnosis at a young age, persons having a substantial family history of breast cancer, ovarian cancer, or similar malignancies, or those who have triple negative breast cancer (TNBC) [ 80 ]. Scientists have also found early alterations in breast tissues that seem healthy before cancer develops, and this could be very helpful in improving early diagnosis of breast cancer [ 81 ]. Ovarian cancer is one of the deadliest gynecological malignancies, with approximately 324,600 new cases and 206,900 deaths reported worldwide each year [ 72 ]. Approximately 23% of ovarian cancer cases are linked to genetic factors. Mutations in the BRCA1 and BRCA2 genes, which cause DNA repair problems, contribute to 65-85% of hereditary ovarian tumors [ 82 ]. Ovarian cancer is now understood as a heterogeneous group of tumors classified by cell of origin, molecular alterations, and clinical behavior [ 83 ]. The term “ovarian cancer” encompasses many types of tumors that can form in the ovaries. The majority are epithelial ovarian cancers (EOCs), further divided into Type I and Type II. These are the most common, but there are less common types, such as stem cell tumors and stromal tumors [ 84 , 85 ]. Type I tumors, such as low-grade serous, mucinous, endometriosis, and clear cell tumors, are slow-growing and begin with recognizable early changes. On the other hand, type II tumors are fast-growing and more dangerous. High-grade serous ovarian cancer (HGSOC) is the most prevalent form, making up over 70-80% of EOCs [ 85 , 86 ]. Epithelial ovarian cancer, exceptionally high-grade serous carcinoma (HGSOC), represents the most lethal form of gynecologic malignancy due to its aggressive biology and late-stage presentation. The disease is characterized by nearly universal TP53 mutations, frequent alterations in BRCA1/2, and profound genomic instability, which collectively drive tumor progression and therapeutic resistance. Inherited genetic predisposition accounts for approximately 20–25% of ovarian cancers, with BRCA1 and BRCA2 mutations being the most significant contributors. Recent advances highlight the fallopian tube epithelium and serous tubal intraepithelial carcinoma (STIC) as key sites of origin, providing new opportunities for early detection and prevention. These molecular insights underscore the importance of comprehensive genetic profiling and precision medicine approaches to improve screening, risk-reduction strategies, and treatment outcomes in ovarian cancer [ 85 , 86 ]. Research suggests that oxidative stress from frequent menstrual cycles could contribute to increasing the chance of ovarian cancer [ 87 ]. The lifetime risk of ovarian cancer is 45–60% for women with a BRCA1 mutation and 11–35% for those with a BRCA2 mutation [ 67 ]. BRCA1 mutations cause ovarian cancer to develop at a younger age than BRCA2 mutations or random cases [ 88 ]. Early detection of ovarian cancer is crucial, as prognosis strongly depends on the stage at diagnosis. Women diagnosed at stage I have a five-year survival rate exceeding 90%, compared to less than 30% in advanced stages. Therefore, improving screening and surveillance strategies, especially in high-risk women carrying BRCA mutations, can significantly reduce mortality [ 85 ].

The BRCA1 gene, located on chromosome 17q21.3, spans approximately 80 kilobases and contains 24 coding exons. It encodes a protein of 1863 amino acids (A.A) that is essential for preserving the integrity of our genetic material [ 14 ]. Functionally, BRCA1 acts as a central coordinator of the cell's response to DNA damage. Upon detecting DNA lesions, it initiates various repair mechanisms, most notably the high-fidelity homologous recombination pathway. Furthermore, BRCA1 plays a crucial part in regulating the cell cycle, temporarily arresting cell growth to allow sufficient time for DNA repair before replication proceeds [ 15 ]. This collaborative effort involves interactions with other key proteins such as p53 and RAD51, ensuring the successful completion of the repair process [ 16 , 17 ] as illustrated in Fig. 1 . Fig. 1 Panel (A) illustrates the structure of the BRCA1 gene, while Panel (B) highlights its role in DNA repair and acts as a tumor suppressor. Panel (C) indicates that BRCA1 induces apoptosis and influences multiple signaling pathways within the cell. Fig. 1 Panel (A) illustrates the structure of the BRCA1 gene, while Panel (B) highlights its role in DNA repair and acts as a tumor suppressor. Panel (C) indicates that BRCA1 induces apoptosis and influences multiple signaling pathways within the cell. Specific structural domains, including the BRCT and the amino-terminal RING domain, underpin the functionality of the BRCA1 protein. The RING domain contains a conserved motif that uses cysteine and histidine residues to coordinate zinc ions. This domain is essential for protein stability and mediating protein-protein interactions. It forms a stable heterodimer with BARD1, which is important for mRNA processing and for E3 ubiquitin ligase activity, a key component of cellular signaling [ 18 ]. The BRCT domain, on the other hand, facilitates the binding of phosphorylated proteins, allowing BRCA1 to interact with a network of proteins involved in DNA repair and cell cycle regulation [ 19 ]. The critical role of these domains in tumor suppression is highlighted by the clustering of many inherited cancer-associated mutations within them. When a genetic mutation renders BRCA1 dysfunctional, the cell's ability to accurately fix DNA damage is impaired, leading to the accumulation of genetic errors and an increased risk of cancer—particularly breast and ovarian malignancies. Thus, the intricate structure and diverse interactions of BRCA1 are indispensable for its role as a “guardian of the genome,” preventing the errors that drive tumorigenesis [ 5 ]. However, the clinical consequences of BRCA1 mutations are not uniform; they are highly dependent on the specific domain affected. For instance, mutations disrupting the RING-BARD1 interface or zinc-binding residues often abrogate E3 ligase activity, leading to profound genomic instability and a strong predisposition to basal-like/triple-negative breast cancer (TNBC) and high-grade serous ovarian carcinoma (HGSOC) [ 20 ]. In contrast, mutations that destabilize the BRCT fold prevent the localization of DNA repair complexes at damage sites, often resulting in aggressive phenotypes that show distinct sensitivities to PARP inhibitors (PARPi) [ 18 ]. Furthermore, the presence of Ovarian Cancer Cluster Regions (OCCRs) within the gene suggests that the mutation's location can skew the phenotypic outcome, altering the relative risk ratio between breast and ovarian malignancies. Distinguishing between these domain-specific mutations is therefore paramount for precision medicine, as it dictates both the prognostic outlook and the selection of targeted therapeutic interventions [ 21 , 22 ]. The BRCA2 gene is a critical component of cellular DNA repair, functioning as a tumor suppressor by maintaining the integrity of genetic material. Located on chromosome 13q12, this gene consists of 27 exons, with the largest spanning 4.9 kilobases. It encodes a protein of 3418 amino acids. Mutations in exon 13 of the BRCA2 gene, along with mutations in exon 11 of the BRCA1 gene, have been linked to ovarian cancer [ 23 ]. A crucial gene for genome integrity, BRCA2 performs several functions in cells, including promoting cellular tolerance to various forms of DNA damage, controlling G2 checkpoints, protecting stalled replication forks, and facilitating homologous recombination ( Fig. 2 ). Similar to BRCA1, BRCA2 acts as a traditional tumor suppressor. A heterozygous mutation in this gene is associated with an increased risk of several cancers, including breast, ovarian, pancreatic, and prostate cancers [ 24 ]. Our mechanistic understanding of BRCA2, including the various partners it interacts with to enable replication, repair, and selection of the DNA double-strand break repair pathway, has advanced through recent studies [ 25 ]. A key function of BRCA2 is its regulation of RAD51. RAD51 is a crucial enzyme that drives strand exchange during homologous DNA recombination (HDR) [ 26 ]. BRCA2 precisely delivers RAD51 to single-stranded DNA (ssDNA) at replication forks or DNA damage sites via its BRC repeats. This critical interaction ensures accurate DNA repair and helps maintain genome integrity [ 27 , 28 ]. Fig. 2 The illustration in Panel (A) details the distinct structure of the BRCA2 gene, including its BRC repeats and DNA-binding domain. The diagram in Panel (B) highlights BRCA2's fundamental roles in preserving genome stability and acting as a tumor suppressor, while Panel (C) indicates its contribution to inducing apoptosis. Fig. 2 The illustration in Panel (A) details the distinct structure of the BRCA2 gene, including its BRC repeats and DNA-binding domain. The diagram in Panel (B) highlights BRCA2's fundamental roles in preserving genome stability and acting as a tumor suppressor, while Panel (C) indicates its contribution to inducing apoptosis. Beyond its structural complexity, the clinical significance of BRCA2 is highly dependent on the location of the mutation within its functional domains. Emerging research indicates a distinct genotype-phenotype correlation; for instance, mutations within the Ovarian Cancer Cluster Region (OCCR), located primarily in exon 11, are associated with a higher relative risk of ovarian cancer than mutations in other regions [ 6 ]. Interestingly, recent studies have also identified a Pancreatic Cancer Cluster Region (PcCCR) situated between positions c.3515 and c.6787. This region significantly overlaps with the OCCR, suggesting a common oncogenic mechanism between ovarian and pancreatic tumors and highlighting how mutations in these specific segments can drive multi-organ cancer susceptibility [ 29 ]. Furthermore, the nature and site of the mutation dictate the therapeutic landscape. Patients with mutations that cause a complete loss of the RAD51-binding domain often exhibit increased sensitivity to PARP inhibitors (PARPi) and platinum-based chemotherapies, as these cells are profoundly deficient in homologous recombination. Consequently, distinguishing between these domain-specific mutations has become a cornerstone of precision oncology, enabling clinicians to tailor surveillance and treatment protocols to each mutation's molecular signature [ 30 ]. Ultimately, mutations in the BRCA2 gene can severely compromise its ability to repair damaged DNA [ 31 ]. When both copies of the gene are mutated, it can lead to Fanconi anemia, a condition characterized by extreme genomic instability [ 32 ]. In summary, the proper function of the BRCA2 gene is essential for DNA repair and the maintenance of genomic stability, acting as a vital safeguard against cellular abnormalities and the accumulation of errors that drive tumorigenesis.

David M. Georgy: Formal analysis, Funding acquisition, Investigation. Hana Nagah Sedeek: Project administration, Validation, Writing – original draft. Nawal Essam Abaza: Conceptualization, Data curation, Investigation, Methodology. Seif Eldeen K. Eldeeb: Investigation, Methodology, Software. Somaya Mohamed Khamis: Software, Validation, Writing – original draft. Mai R. Elgamil: Conceptualization, Data curation, Software, Writing – original draft. Raghda W. Magar: Supervision, Writing – review & editing.

Recent advances in multi-omics technology, which integrate data from transcriptomics, genomics, proteomics, metabolomics, and other omics, have become critical for interpreting the complex molecular mechanisms underlying disease. Multiomics provides a comprehensive view of biological systems and enables characterization of the TME by capturing genomic mutations, protein interactions, and metabolic changes. This will be used to identify different tumor types, cancer progression, and metastasis mechanisms, and to develop customized solutions for each subtype [ 143 ]. Emerging therapeutic strategies increasingly focus on targeting components of the TME in combination with targeted tumor therapies to reduce metastasis, tumor progression, and chemotherapy resistance [ 11 ]. The development of anticancer drugs is a complex, multifactorial process that requires a robust pharmacological framework (Pharmacovigilance) during preclinical and experimental studies [ 144 ]. Multiomics approaches are crucial for drug discovery, as they help identify novel drug targets. A comprehensive understanding of cancer complexity and tumor heterogeneity is achieved to develop more effective diagnostic tools and therapies. This is essential for early diagnosis and predicting therapeutic response [ 143 ]. To bridge the gap between genetic mutations and clinical outcomes in gynecological malignancies, integrating multi-omics frameworks has become indispensable. Beyond identifying BRCA1/2 mutations, a multi-layered analysis incorporating genomics, proteomics, and metabolomics reveals a complex landscape of molecular interactions [ 143 ]. A key area of interest is the ubiquitination-mediated regulation of DNA repair proteins. In ovarian cancer, dysregulated ubiquitination pathways, particularly involving E3 ubiquitin ligases, can alter the stability of both wild-type and mutant BRCA proteins [ 145 ]. Recent trends in drug discovery emphasize using these multi-omic signatures to identify undruggable targets, moving beyond simple genetic screening to functional proteomic [ 146 ]. These ubiquitination-related markers are emerging as critical prognostic tools; their expression levels provide high-value predictive insights into patient survival and the metabolic fate of oncogenic proteins [ 147 ]. By influencing the cellular response to PARP inhibitors, these markers are refining personalized treatment strategies and paving the way for the next generation of precision oncology [ 148 ]. Coumarin thiosemicarbazone hybrids, acting as BRCA1 mimetics, represent a new paradigm for ER-positive breast cancer, complementing existing therapeutic advancements. These mimetics bypass BRCA1 deficiency by competing with cyclin D1 for ERα binding. This inhibition downregulates proliferative drivers, such as cyclin D1 and BCL2, thereby suppressing tumor growth [ 149 ]. Unlike traditional antiestrogen therapies, BRCA1 mimetics offer a unique mode of action that overcomes hormonal resistance, marking a revolutionary frontier in precision medicine [ 150 ]. Natural Killer (NK) cells are key components of the innate immune system and play an important role in tumor immunity, where their functional state is regulated by the balance between activating and inhibitory checkpoints. Several immune checkpoint molecules on NK cells have been identified, including TIGIT, KIRs, and NKG2A, which hold great clinical therapeutic potential [ 151 ] by transducing signals that regulate cytotoxicity and cytokine secretion [ 152 ]. Targeting NK cells in solid tumors has shown remarkable progression in preclinical research, particularly in advanced ovarian cancer. Research has investigated the DNAM-1/1/TIGIT/CD96 signaling axis, revealing that while NK cells from advanced patients show an immunosuppressive phenotype, targeted blockade of TIGIT can specifically enhance the effector functions of CD56dim NK cells [ 152 , 153 ]. This precision is currently applied in the management of HER2-positive breast cancer (BC) through molecules like trastuzumab, pertuzumab, lapatinib, and T-DM1. Trastuzumab and pertuzumab inhibit the MAP kinase and PI3K–Akt signaling pathways to reduce tumor proliferation [ 154 ], and dual blockade has been shown to act as a radiosensitizer [ 155 ]. Preclinical studies confirm that HER2 overexpression reduces radiosensitivity in BC cell lines like MCF-7 and MDA-MB-231, whereas anti-HER2 therapy can reverse this radioresistance [ 156 ]. In clinical practice, trastuzumab is frequently administered concomitantly with locoregional radiotherapy (RT) [ 157 ]. Although cumulative cardiac toxicity is a concern, major trials like the NCCTG Phase III Trial N9831 (982 patients) demonstrated that this combination does not significantly increase cardiac events or acute skin reactions [ 158 , 159 ]. Recent data further support the safety of combining RT with dual HER2 inhibition, showing favorable tolerance with only mild, expected effects on LVEF [ 160 , 161 ]. This safety profile is also consistent in patients with brain metastases receiving concurrent RT and trastuzumab [ 162 ]. Integrating the aforementioned advancements in nanotechnology with targeted molecular therapy offers a promising frontier to bypass current therapeutic failures. Evidence indicates that miR-181a acts as a potent oncogenic driver in BRCA-deficient breast and ovarian malignancies, correlating with tumor aggressiveness. Mechanistically, miR-181a induces stem-like characteristics and immune evasion, thereby driving PARPi resistance by activating the PTEN/AKT and TGF-β pathways [ 163 ]. Furthermore, plant-derived exosome-like nanoparticles (PELNs) have been established as highly effective and biocompatible delivery platforms [ 164 ]. Building on these findings, we propose a novel strategy: using PELNs to deliver anti-miR-181a to specifically neutralize the miR-181a/AKT axis, thereby restoring PARPi sensitivity and overcoming recalcitrant drug resistance.

BRCA1 functions as a transcriptional regulator that controls genes involved in DNA damage repair (DDR) by interacting with various complexes and proteins, including histone deacetylase complexes, DNA polymerase II holoenzyme, c-Myc, and p53 [ 52 ]. BRCA1 reduces the transcription of c-Myc, a known transcriptional activator, while simultaneously promoting the transcription of p53-responsive genes near their promoters. However, this regulatory effect is not observed in BRCA1-deficient mutants. In most cell lines, increased BRCA1 expression does not directly induce apoptosis; instead, it enhances the expression of p53-dependent genes involved in DNA repair and cell cycle arrest [ 53 ]. While the transcriptional function of BRCA2 is less apparent, some evidence suggests a connection to other transcription-related proteins, such as Smad3. Smad3 and BRCA2 interact both functionally and physically, both possessing transcription-activation domains. Smad3 forms a complex with BRCA2 both in vitro and in vivo, and the two proteins work together to regulate gene transcription [ 54 ].

This review has no ethical approval; thus,this is a collection of author studies.

This review has no ethical approval; thus,this is a collection of author studies.

No funding

Approximately 5–10% of all breast cancer cases are hereditary, commonly associated with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2, as well as the PALB2 gene (partner and localizer of BRCA2) [ 35 ]. When functioning correctly, these genes are crucial for DNA repair, and a harmful mutation can significantly increase a person's lifetime risk of developing breast cancer. For example, up to 80% of individuals with a BRCA1 mutation may develop breast cancer, and these mutations are strongly linked to the aggressive triple-negative breast cancer subtype. While less common, BRCA2 pathogenic variants are more frequently associated with estrogen receptor-positive breast cancer [ 36 ]. The likelihood of developing breast cancer from these mutations significantly increases with age, rising from 33% to 58% after the age of 70. PALB2 mutations are now recognized as a medium to high-risk factor for hereditary breast cancer, with phenotypic aspects comparable to BRCA1/2 mutations. However, a unique and substantial danger of PALB2 mutations is that a single mutation can lead to diverse cancer morphologies, highlighting its critical role in maintaining genomic stability [ 37 ].

Genetic changes that occur in any of the body's cells are known as somatic mutations, except in germ cells (sperm and egg cells). These mutations are acquired during an individual's lifetime and are not inherited [ 63 ]. In the BRCA genes, these somatic mutations occur sporadically within individual cells, triggered by factors such as errors in DNA replication during cell division, exposure to radiation, or certain chemicals [ 64 ]. For the individual, somatic BRCA mutations can initiate cancer development if they arise in tumor-forming cells by disrupting the normal DNA repair functions of BRCA proteins, potentially leading to genomic instability and increased cancer risk in affected tissues [ 65 ]. Notably, somatic BRCA mutations present in a tumor can also influence cancer treatment strategies, as these tumors may exhibit sensitivity to therapies like PARP inhibitors [ 66 , 67 ]. However, because they arise in somatic cells, these mutations are not passed on to future generations, remaining confined to the lineage of the initially mutated cell. Germline mutations are genetic alterations that occur in germ cells, specifically sperm or egg cells. Consequently, these mutations are inherited from a parent and are found in every cell of the offspring's body from the moment of conception [ 68 ]. An individual carrying a germline BRCA mutation has inherited it directly from one or both of their parents. This inherited mutation significantly elevates their lifetime risk of developing specific cancers, most notably breast, ovarian, prostate, and pancreatic cancers, with the precise risk level depending on the type of mutation and if it affects BRCA1 or BRCA2. Because mutation is present in all cells of the body, this increased cancer risk can affect multiple tissues and organ systems [ 69 ]. Furthermore, germline mutations are heritable, meaning that a person with a germline BRCA mutation has a 50% chance of passing this mutation on to each of their children.

Determining gBRCAm status prior to clinical intervention is crucial; current evidence indicates that this status significantly influences both systemic and surgical treatment strategies for patients with breast cancer. Clinical practice recommendations further support the role of gBRCAm testing in therapeutic decision making, in addition to its importance for risk management and cascade testing [ 95 , 96 ]. The evolution of breast cancer management reflects the integration of conventional cytotoxic chemotherapy with targeted, immune-based, and gene-directed approaches. The following Table (2) summarizes the principal treatment modalities, their mechanisms of action, representative agents, and clinical relevance in breast cancer management. Table 2 Overview of current therapeutic strategies in breast cancer: mechanisms, key agents, and clinical significance. Table 2 Treatment Mechanism/Efficiency Key Examples/Significance Additional Insight Reference chemotherapy Cytotoxic agents target rapidly dividing cells; effective against gBRCAm BC. Platinum/Anthracycline-Taxane: Standard regimens for advanced and early-stage disease, respectively. Provides a robust, established pathway, particularly potent in tumors with DNA repair deficiency, though with higher systemic toxicity. [ [97] , [98] , [99] , [100] ] PARP Inhibition Exploits DNA repair deficits in gBRCAm cells (Synthetic Lethality) to induce cell death. Olaparib, Talazoparib: Approved for advanced gBRCAm or HER2-negative BC. Represents a major therapeutic advance for gBRCAm patients, offering a targeted, often less toxic, alternative to traditional chemotherapy. [ 92 , 93 ] Immune Therapy Re-engages the patient's immune system to mount a durable anti-tumor response. Efficacy correlates with the presence of Tumor-Infiltrating Lymphocytes (TILs). Immune Checkpoint Inhibitors: Show significant therapeutic benefit, especially in Triple-Negative Breast Cancer (TNBC). Highly impactful in aggressive tumors like TNBC, offering a novel avenue where other targeted options are limited. It serves as a strong foundation for future combination therapies. [ 94 ] Targeted Therapy (HER2) Monoclonal antibody-mediated receptor antagonism against the HER2 protein. Trastuzumab (Herceptin): The gold standard for HER2-positive malignancies since its FDA approval in 1998. This therapy is considered one of oncology's greatest successes, transforming HER2-positive cancer from a poor prognosis to a manageable condition. [ 101 ] Overview of current therapeutic strategies in breast cancer: mechanisms, key agents, and clinical significance.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, transforming treatment outcomes across multiple malignancies. ICIs are monoclonal antibodies that target key immune regulatory pathways, primarily the CTLA-4/CD28 and PD-1/PD-L1 axes, thereby enhancing anti-tumor immune responses. Immunotherapy has become the gold standard for treating a wide range of cancers, including both solid tumors and hematological malignancies, and is used in both therapeutic and palliative settings [ 102 , 103 ]. In the context of BRCA-mutant cancers, the efficacy of ICIs is uniquely dictated by the immunological features of their tumor microenvironment (TME). While genomic instability in these tumors often leads to high neoantigen loads, rendering them ‘immunologically hot', the human microbiome acts as a pivotal regulator of these dynamics. Microbes influence the TME by modulating dendritic cell maturation and systemic metabolic reprogramming, which are essential for T-lymphocyte activation [ 13 ]. Despite these therapeutic benefits, ICIs are linked to immune-related adverse events (irAEs) that differ from the usual cytotoxic chemotherapy side effects. The incidence of irAEs depends on the malignancy, the drug used, and the patient's characteristics. (irAEs) are typically associated with inflammatory responses generated by the immune system against specific organs and tissues. Some research indicates that several immune mechanisms may contribute to the development of irAEs, including the release of proinflammatory cytokines (such as interleukin-17), activation of autoreactive T cells, and the production of autoantibodies [ [104] , [105] , [106] , [107] ]. Currently, no validated biomarkers in clinical practice reliably predict which patients will develop immune-related adverse events (irAEs). However, retrospective observational studies have identified several factors associated with an increased risk of irAEs, including female sex, specific somatic and germline genetic features, distinct gut microbiome compositions, and specific circulating biomarkers. Although uncommon, immune checkpoint inhibitors can occasionally cause sudden and even life-threatening toxicities [ 108 , 109 ]. Future research is increasingly focused on enhancing prediction, prevention, and management of immune-related adverse events (irAEs). A primary goal is the discovery of dependable biomarkers, including genomic, proteomic, and microbiome signatures, that can identify patients at greater risk before starting immunotherapy [ 110 , 111 ]. Using synthetic lethality, a class of targeted medications called poly ADP-ribose polymerase (PARP) inhibitors, between homologous recombination repair (HRR), which is commonly compromised in malignancies with BRCA1/2 mutations, or other variables impacting DNA damage response (DDR), and single-strand breaks mediated by PARP. Presently, ovarian cancer and breast cancer are among the solid malignancies against which PARPis have shown promising clinical effectiveness [ 61 , 112 , 113 ]. However, their clinical applications face significant challenges because of the emergence of PARPi resistance and their poor effectiveness in cancers without BRCA1/2 mutations. The study highlights the urgent need for new approaches to enhance PARPis' anti-cancer activities and combat medication resistance. Combining PARPis with other drugs targeting particular pathways for tumor growth, survival, or immune evasion is a promising approach. The study discusses the challenges of using PARPis in combination with other medications for solid tumors [ [114] , [115] , [116] ]. To understand these challenges, it is essential to consider the biological mechanisms underlying PARPi activity. ADP-ribosyl transferases (ARTs) are nuclear enzymes that catalyze the transfer of ADP-ribose units to specific target proteins, a process crucial for numerous cellular functions, including cell division, differentiation, DNA damage detection and repair, metabolism, and stress response. Among the 17 members of the ADP-ribosylation enzyme superfamily, PARP1, PARP2, PARP5A, and PARP5B can synthesize poly (ADP-ribose) chains. The inhibition of these enzymes by PARPis forms the basis of their therapeutic mechanism, particularly in tumors with defective DNA repair pathways. While effective in such contexts, expanding their benefit to non-HRD-related cancers remains a major focus of ongoing research [ 117 , 118 ]. Findings from major phase III clinical trials—including SOLO1 (olaparib), PRIMA (niraparib), VELIA (veliparib), and ATHENA-MONO (rucaparib)—suggest that the clinical efficacy of PARPis in homologous recombination deficiency (HRD) negative patients is notably lower than in BRCA-mutated individuals. These results imply that therapeutic benefit varies according to the tumor's underlying genetic repair capacity. Moreover, secondary genetic or epigenetic alterations that restore HRR activity represent a key mechanism of acquired resistance. These “reversion mutations” effectively repair the original BRCA deficiency, allowing the cell to fix double-strand breaks and negating the synthetic lethal effect of the inhibitor. This restoration poses a major unmet clinical need; however, PARPi adverse effects may restrict medication effectiveness and patient tolerability. Consequently, combination treatment strategies are being developed to bypass current barriers, enhance therapeutic response, and mitigate medication resistance [ [119] , [120] , [121] , [122] , [123] , [124] ]. Emerging evidence suggests that PARPi resistance can arise independently of HRR restoration, primarily through the active stabilization of the replication fork. In PARPi-sensitive, BRCA-deficient cells, the loss of BRCA1/2 functions leads to the catastrophic degradation of stalled replication forks by nucleases such as MRE11, DNA2, and PTIP, converting them into lethal double-strand breaks (DSBs) and triggering genomic collapse [ 120 ]. However, resistant tumor cells evolve sophisticated alternative strategies to maintain fork integrity and evade synthetic lethality. This is primarily achieved by preventing nuclease recruitment; for instance, the loss of proteins such as PTIP or EZH2 blocks MRE11's access to DNA, thereby halting degradation even in the absence of functional BRCA proteins [ 125 ]. Additionally, resistant cells often modulate chromatin remodelers such as SMARCAL1, ZRANB3, and HLTF to promote “fork reversal.” This process converts three-way junctions into four-way “chicken-foot” structures, which are inherently more stable and less prone to nucleolytic attack [ 126 ]. Furthermore, cells may employ alternative pathways to recruit RAD51 to stalled forks; once loaded, RAD51 functions as a physical shield, coating nascent DNA strands to protect them from nucleolytic degradation [ 127 ]. This resistance phenotype is further bolstered by the downregulation of Schlafen 11 (SLFN11), which allows cancer cells to bypass the replication blocks commonly induced by DNA damage. By preventing the conversion of stalled forks into lethal chromosomal breaks, these mechanisms enable tumors to survive and proliferate despite a profound deficiency in homologous recombination, representing a significant hurdle in clinical precision oncology [ 128 ]. Beyond genetic reversions, a critical non-genetic mechanism of resistance involves the active reduction of intracellular drug bioavailability by overexpressing ATP-binding cassette (ABC) transporters. Among these, P-gp/MDR1 (encoded by ABCB1) is the most clinically significant [ 129 ]. Functioning as a high-capacity efflux transporter, P-gp exhibits a high affinity for specific PARP inhibitors, such as olaparib and rucaparib, actively ejecting them from the cytoplasm. This efflux prevents the drugs from reaching the nucleus in concentrations sufficient to achieve “PARP trapping” on DNA—a process essential for triggering synthetic lethality in HR-deficient cells [ 130 ]. Clinical evidence, particularly in recurrent high-grade serous ovarian cancer, suggests that ABCB1 upregulation is often induced by prior chemotherapy exposure or genomic translocations that place the gene under the control of constitutive promoters. Interestingly, the impact of these pumps varies across the PARPi class: while olaparib and rucaparib are highly susceptible to efflux, others, such as veliparib and AZD2461, appear less affected. This differential sensitivity suggests that monitoring a patient's transporter expression profile could be vital for tailoring inhibitor selection to circumvent pharmacokinetic resistance and improve therapeutic outcomes [ 131 ]. The limited efficacy of PARPis in HRD-negative tumors and the growing problem of acquired resistance have prompted the exploration of multifaceted immunomodulatory strategies. Recent studies highlight that combining PARPis with stimulator of interferon genes (STING) agonists can effectively remodel the tumor microenvironment (TME), converting it from an immunosuppressive to an immune-active state. This shift enhances macrophage polarization toward an M1 phenotype, stimulates dendritic cell activation, and promotes infiltration of cytotoxic T cells and natural killer (NK) cells, collectively amplifying anti-tumor immunity [ 132 ]. Preclinical evidence in breast and ovarian cancer models demonstrates that these combinations can overcome PARPi resistance and restore therapeutic sensitivity. Furthermore, combining PARPis with CDK4/6 inhibitors represents another promising approach, as it induces therapy-induced senescence and potentiates cGAS–STING signaling, thereby enhancing immune recognition of tumor cells. Parallel efforts are focusing on epigenetic and miRNA modulation, targeting suppressors of the STING pathway such as miR-181a, to reinstate innate immune activation [ [133] , [134] , [135] ]. Advances in nanotechnology-based delivery systems, including STING-activating nanoparticles, may further optimize drug delivery, reduce systemic toxicity, and strengthen immune activation. Finally, the development of dynamic biomarkers—such as signatures of STING pathway activation, NK cell infiltration, and early markers of homologous recombination restoration will be essential for guiding patient selection and monitoring therapeutic response [ [136] , [137] , [138] ]. Breast cancer management is multifactorial, determined by clinical status, tumor subtype, and disease stage. Standard treatment integrates surgery, chemotherapy, radiation, hormonal and targeted therapies, immunotherapy, and bone-modifying agents. Despite this multimodal approach, clinical challenges persist, including systemic toxicity, emerging drug resistance, and long-term adverse effects that significantly impact patients' quality of life [ 139 ]. Genome-editing approaches that alter DNA sequences are highly beneficial for cancer treatment. Endonucleases are used to replace or repair double-stranded DNA, thereby enhancing the effectiveness of these methods. Because of its broad range of applications, adaptability, ease of use, and efficiency, the CRISPR/Cas9 system is a widely used genome-editing tool, as it can target genes without protein re-engineering. Investigations on the pathophysiology of breast cancer, CRISPR/Cas9 is used to target genes implicated in unchecked cell proliferation and tumor development. This enables the examination of mutations in these genes and, if necessary, their correction and regulation using the potent CRISPR/Cas9 system, thereby preventing tumor formation and promoting naturally regulated cell growth [ 140 , 141 ]. The complexity and incredible diversity of the tumor microenvironment pose critical challenges to the clinical application of therapeutic strategies. Specifically, this environment contains numerous cells with unique immunological properties that exhibit strong defensive responses against external substances. However, cancer cells often lack specific markers, making precise drug delivery difficult. At the same time, malignant tumors exhibit a high propagation capacity, significant drug resistance, and strong radiation resistance. These characteristics severely impair the effectiveness of conventional treatments such as surgery, chemotherapy, and radiotherapy, exacerbating the suffering of cancer patients [ 142 ].

Mutations in the BRCA1 and BRCA2 genes largely shape our understanding of the development of breast and ovarian cancer. BRCA1 and BRCA2 are integral components of a larger network of proteins involved in HRR, including ATM, PALB2, and RAD51. Mutations in these other HRR genes can also lead to homologous recombination deficiency (HRD) and increased cancer risks. Regarding breast and ovarian cancer linked to a BRCA mutation, chemotherapy is a standard treatment option. However, chemotherapy faces challenges due to its high toxicity and severe side effects. Advances in targeted therapies, genetic testing, and personalized care have significantly improved patient management, while immunotherapy, gene therapy, and early detection techniques represent promising future directions. The introduction of immune checkpoint inhibitors (ICIs) and PARP inhibitors (PARPis) has transformed treatment for BRCA-mutated and other solid tumors; however, challenges remain. ICIs enhance anti-tumor immunity but are limited by immune-related adverse events (irAEs), emphasizing the need for predictive biomarkers and individualized approaches. PARPis exploit defects in homologous recombination repair, yet resistance mechanisms and reduced efficacy in HRD-negative tumors highlight the importance of combination strategies. Emerging techniques, such as combining PARP inhibitors with ICIs, STING agonists, CDK4/6 inhibitors, or epigenetic modulators, can remodel the tumor microenvironment, restore therapeutic sensitivity, and enhance immune responses. Complementary advances in nanotechnology-based drug delivery, dynamic biomarker development, and CRISPR/Cas9 genome editing offer the potential to correct BRCA mutations, prevent tumor growth, and restore normal cell regulation. Overall, integrating targeted molecular therapies, immunotherapy, and genome-editing technologies, supported by interdisciplinary research and personalized treatment strategies, will be essential to maximize efficacy, minimize toxicity, and improve outcomes in BRCA-associated and other malignancies.

During the preparation of this work, the authors used Gemini and Quillbot in order to enhance the linguistic flow, technical terminology, and structural connectivity of the manuscript. These tools were utilized solely for language editing and stylistic refinement. Following this process, the authors meticulously reviewed, verified, and edited the generated content to ensure scientific accuracy and take full responsibility for the final integrity of the published article.

Aberrations in cell cycle regulation are frequently observed in breast cancer (BC) and are often associated with changes in proteins that mediate the G1/S transition [ 55 ]. However, the expression of proteins involved in the cell cycle in BC with BRCA1 or BRCA2 mutations remains poorly understood. Furthermore, BRCA1-mutated cancers are characterized by a high incidence of p53+ and hormone receptor negativity, whereas BRCA2-mutated cancers show the opposite. Moreover, type D cyclins (D1, D3), their associated CDKs, and the CDKIs p16, p21, and p27 indicate that BRCA1 expression is lower than that of BRCA2 in carcinomas [ 56 ]. In addition, the ER+/p53 phenotype, characteristic of the majority of BRCA2 carcinomas, showed lower Ki-67 expression and increased levels of cell-cycle proteins [ 57 ]. Furthermore, the expression of cyclin D1, which is induced by estrogen, was less prevalent in carcinomas with BRCA1 mutations than in BRCA2-mutated carcinomas. Also, BCL2 overexpression was observed in BRCA2-mutated carriers, with a strong association with ER + status. Conversely, BRCA1 tumors showed increased caspase 3 levels, a cytosolic enzyme that becomes active only in apoptotic cells. Additionally, another important gene and risk factor for inherited BC is PALB2. Notably, a mutation in two PALB2 alleles causes Fanconi anemia, increasing a child's susceptibility to pediatric cancers. Finally, a mutation in one allele causes familial pancreatic and breast cancer, women's ovarian cancer, in addition to men's prostate cancer [ 58 ].

The current review is a systematic review that collected literature from PubMed, Scopus, ScienceDirect, Web of Science, and Google Scholar. The literature collection timeframe was 2000-2025, and the total number of references was 164. To manage references efficiently, we used the APA style in EndNote 20.5. The study selection process is summarized in the PRISMA 2020 flow diagram. • Studies investigating BRCA1/BRCA2 gene mutations and their roles in gynecologic cancers. • Research addressing mechanisms of DNA repair, PARP inhibitors, immunotherapy, or gene therapy. • Human studies and relevant in vitro or in vivo experimental models. • Articles published in English between 2000 2025. Studies investigating BRCA1/BRCA2 gene mutations and their roles in gynecologic cancers. Research addressing mechanisms of DNA repair, PARP inhibitors, immunotherapy, or gene therapy. Human studies and relevant in vitro or in vivo experimental models. Articles published in English between 2000 2025. • Non-English publications, editorials, conference abstracts without complete data, or duplicate studies. • Papers focused on non-gynecologic cancers or unrelated genetic syndromes. • Case reports with insufficient molecular or therapeutic data. Non-English publications, editorials, conference abstracts without complete data, or duplicate studies. Papers focused on non-gynecologic cancers or unrelated genetic syndromes. Case reports with insufficient molecular or therapeutic data. All identified records were screened by two independent reviewers. Titles and abstracts were initially assessed for relevance, followed by full-text evaluation of eligible papers. Disagreements were resolved by consensus with a third reviewer. We conducted a risk of bias (RoB) assessment for all included studies to evaluate the internal validity and to inform the interpretation of results. Given the heterogeneous study designs in our review (clinical trials, cohort studies, case-control, and experimental models), we used a two-pronged approach. 1. For randomized controlled trials (RCTs), we used the Cochrane Risk of Bias 2 (RoB 2) tool, assessing: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. 2. For non-randomized studies of interventions and observational studies, we used ROBINS-I , assessing bias due to confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of reported results. For randomized controlled trials (RCTs), we used the Cochrane Risk of Bias 2 (RoB 2) tool, assessing: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. For non-randomized studies of interventions and observational studies, we used ROBINS-I , assessing bias due to confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of reported results. Implementation: Two reviewers independently assessed the risk of bias for each included study. Disagreements were resolved by discussion and, when necessary, by consulting a third reviewer. Results were summarized in a table and narratively described in the text. Summary of findings. • Out of the included studies (n = 164), the majority were observational/preclinical reports with varying reporting quality. Representative assessment showed that: o High risk of bias (select domains) was observed mainly in older observational studies with incomplete outcome reporting and unclear confounding control. o Moderate risk was common in cohort studies with confounder adjustment. o Low risk was observed in well-conducted RCTs and recent prospective studies with transparent methodology. Out of the included studies (n = 164), the majority were observational/preclinical reports with varying reporting quality. Representative assessment showed that: o High risk of bias (select domains) was observed mainly in older observational studies with incomplete outcome reporting and unclear confounding control. o Moderate risk was common in cohort studies with confounder adjustment. o Low risk was observed in well-conducted RCTs and recent prospective studies with transparent methodology. High risk of bias (select domains) was observed mainly in older observational studies with incomplete outcome reporting and unclear confounding control. Moderate risk was common in cohort studies with confounder adjustment. Low risk was observed in well-conducted RCTs and recent prospective studies with transparent methodology. Implications: The identified risks of bias may weaken causal inferences and contribute to heterogeneity in reported outcomes. We interpreted the overall evidence, considering these limitations, and avoided overgeneralization when high- or unclear-risk domains predominated.

BRCA1 and BRCA2 are fundamental human genes acting as tumor suppressors. They produce proteins essential for a precise DNA repair process called homologous recombination repair (HRR) [ 1 ]. This pathway has a critical system for accurately repairing double-stranded DNA breaks, which can occur during routine DNA replication or in response to environmental stressors. By ensuring the faithful repair of these potentially damaging lesions, BRCA1 and BRCA2 maintain genomic stability and prevent the accumulation of errors that could lead to uncontrolled cell growth and tumor development [ 2 ]. BRCA1 and BRCA2, located on chromosomes 17q21 and 13q12, respectively, were discovered in the mid-1990s as the first genes linked to inherited susceptibility for ovarian and breast cancer [ 3 ]. While these genes are present in all human beings, mutations in them significantly increase an individual's risk of developing cancer, leading to Hereditary Breast and Ovarian Cancer (HBOC) syndrome. In addition to early-onset breast and ovarian cancer, HBOC syndrome is associated with an increased risk of pancreatic, stomach, laryngeal, fallopian tube, and prostate cancer. A lifetime risk of 60–80% for breast cancer and 20–40% for ovarian cancer is associated with the presence of mutations in either BRCA1 or BRCA2 genes [ 3 , 4 ]. Deficient DNA repair mechanisms, often caused by mutations in BRCA1 and BRCA2, result in the accumulation of damaged DNA and genomic instability, significantly increasing cancer risk [ 5 ]. The spectrum of BRCA mutations is extensive, with numerous distinct alterations within the gene sequence, each potentially associated with a different level of cancer susceptibility [ 6 ]. BRCA1 and BRCA2 are integral components of a larger network of proteins involved in HRR, including genes like ATM, PALB2, RAD51, and CHEK2. Mutations in these other HRR genes can also lead to homologous recombination deficiency (HRD) and increased cancer risks [ 7 ]. The understanding of HRD now extends beyond specific BRCA mutations to represent a broader functional impairment in DNA repair. This broader definition of HRD serves as a crucial biomarker for personalized cancer risk assessment, guiding preventive strategies, and predicting therapeutic responses [ 8 ]. ​A key example of this is the use of PARP inhibitors, a class of drugs that selectively target and kill tumor cells that have this repair defect. Recent advances in targeted treatments, such as PARP inhibitors and immunotherapy, are showing great promise in treating BRCA-deficient tumors. These therapies leverage the very defect that drives tumor growth to kill cancer cells, representing a significant step forward in personalized cancer medicine [ 8 , 9 ]. Beyond genetic mutations, it has become increasingly evident that tumor complexity is closely linked to the tumor microenvironment (TME) and is not solely determined by cancer cells' intrinsic properties. The dynamic nature of the TME involves cellular interactions, chemokine networks, and reciprocal interactions between tumor cells and surrounding stromal cells, including endothelial cells, cancer-associated fibroblasts, and immune cells [ 10 , 11 ]. Furthermore, emerging evidence highlights the pivotal role of the tumor microbiome in modulating these interactions; local and systemic microbial populations can significantly influence immune surveillance and the metabolic landscape of the TME. These interactions contribute to the onset, progression, and metastasis of cancer, as well as immune evasion, angiogenesis, and chemoresistance [ 12 , 13 ]. This systematic review explores the essential roles of BRCA1 and BRCA2 in DNA repair, how their mutations contribute to inherited ovarian and breast cancer, and potential treatments targeting BRCA-deficient tumors. The article also discusses recent advances in BRCA-targeted treatments, including PARP inhibitors, nanotechnology-based drug delivery, dynamic biomarker development, and immunotherapy, to maximize efficacy, minimize toxicity, and improve outcomes in BRCA-associated and other malignancies.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.