Our previous data showed that carriers of germline BRCA1/2 pathogenic variants (PV) with breast cancer (BC) treated with mastectomy without post-mastectomy radiation therapy (PMRT) had higher rates of loco-regional recurrence (LRR) compared to those who underwent PMRT or breast-conserving therapy (BCT), despite earlier stage BC. Our aim was to verify our previous findings in a larger cohort.

Clinical data were extracted from the medical records of BRCA1/2 mutation carriers with BC, treated at a single institution between 1/2006 and12/2022. The data included demographics, treatment modalities, and BC outcomes.

A total of 464 patients with 484 primary tumors were analyzed. Of these, 48.3% mastectomies were performed: 66% (154) without PMRT (non-PMRT) and 34% (80) with PMRT; 51.8% (250) underwent BCT. The non-PMRT group had earlier disease stages at diagnosis (77.3% were Tis and T1N0 stage) compared to the PMRT and BCT groups (3.8% and 45%, respectively, p < 0.001). During the study period with a median follow-up time of 75 months (range 12-211), the LRR rate was 13% (20/154) in the non-PMRT cohort compared with 1.25% (1/80) in the PMRT group (p = 0.003), and 6.4% (16/250) in the BCT group (p = 0.03). Cumulative incidence of LRR at 5 and 15 years was 14.7%, and 16.6% in the non-PMRT, compared to 5.1% and 35% in the BCT group, respectively (p = 0.081). No significant difference in overall survival was observed (p = 0.202).

The timing and rates of LRRs differ according to the loco-regional therapy, which might indicate a different etiology driving these events.

BRCA1 is a complex tumor suppressor protein involved in multiple critical cellular processes, e.g., DNA double-strand break repair, cell cycle checkpoint, etc. BRCA1-depleted cells show decreased homologous recombination (HR) and promote error-prone non-homologous end joining for DNA damage repair. Holliday junction (HJ) is an essential intermediate of DNA damage repair mechanism through HR. BRCA1 protein has high affinity for HJ and recruits several proteins to DNA damage site. Nonetheless, questions remain regarding the binding of BRCA1 protein with HJ. Does BRCA1 protein show preference for isomers of HJ? Why do specific mutations in BRCA1 protein lead to impaired DNA damage repair? Do those amino acids play any role in BRCA1-HJ interactions? Using single-molecule Fluorescence Correlation Spectroscopy, we showed that BRCA1 prefers an open-planar conformation of HJ and has a 10-fold lesser affinity for stacked HJ. The preference for an open-planar structure is independent of the nucleotide sequence at the branch point. Molecular docking and all-atom molecular dynamics simulation unraveled that primarily charged and polar residues in the DNA binding region from exon 11 of BRCA1 participated in the interaction. Most of those amino acids are places for missense changes. Further computational studies revealed that mutating these residues disrupted the interaction.

Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment landscape for patients suffering from BRCA1-mutated breast and ovarian cancers. However, responses are not durable. We demonstrate that treatment with PARPi, niraparib, increases programmed death-ligand 1 (PD-L1) expression in BRCA1-deficient cancer cells, contributing to immune evasion. To circumvent this, we developed P-selectin-targeted poly (lactic-co-glycolic) acid (PLGA)-poly (ethylene glycol) (PEG)-based nanoparticles (NPs) encapsulating PARP and PD-L1 inhibitors at a synergistic ratio. To further enhance tumor targeting, we leveraged radiation-induced P-selectin upregulation in BRCA1-deficient cancer cells and their associated angiogenic endothelial cells, improving NP accumulation in the primary tumors and hard-to-target metastatic sites, including brain metastasis. Using a combination of traditional 2-dimensional (2D) cell cultures, advanced 3-dimensional (3D) spheroids, tumor-on-a-chip platforms, and in vivo models, we demonstrate the enhanced accumulation and efficacy of the radiation-guided P-selectin-targeted NPs in primary and brain-metastatic BRCA1-deficient tumors.

Homologous recombination deficiency (HRD) leads to genomic instability, and patients with HRD can benefit from HRD-targeting therapies. Previous studies have primarily focused on identifying HRD biomarkers using data from a single technology. Here we integrated features from different genomic data types, including total copy number (CN), allele-specific copy number (ASCN) and single nucleotide variants (SNV). Using a semi-supervised method, we developed HRD classifiers from 1404 breast tumours across two datasets based on their BRCA1/2 status, demonstrating improved HRD identification when aggregating different data types. Notably, HRD-positive tumours in ER-negative disease showed improved survival post-adjuvant chemotherapy, while HRD status strongly correlated with neoadjuvant treatment response. Furthermore, our analysis of cell lines highlighted a sensitivity to PARP inhibitors, particularly rucaparib, among predicted HRD-positive lines. Exploring somatic mutations outside BRCA1/2, we confirmed variants in several genes associated with HRD. Our method for HRD classification can adapt to different data types or resolutions and can be used in various scenarios to help refine patient selection for HRD-targeting therapies that might lead to better clinical outcomes.

In March 2020, a nationwide population carrier screening for BRCA1/2 pathogenic variants among Ashkenazi Jewish women was initiated in Israel. We aimed to assess views regarding the program among professionals who provide oncogenetic counseling for detected carriers.

An online survey was distributed to clinical geneticists and genetic counselors.

The participants' impression was that most carriers did not comprehend the implications of a positive result when deciding to take the test. Some carriers, in retrospect, regretted taking it. Some had a known mutation carrier in the family, and some had a family history that justified a broader test (and so should not have been tested through the screening program). Eight survey participants (29%) reported they were initially against the screening program, but half of them are currently in favor of it. Most participants are unsatisfied with the way the screening is conducted and suggested various improvements. Emotional distress of carriers, as assessed by participants, was higher for those detected by the screening program, compared to those tested after oncogenetic counseling. No association was found between the age, profession, and prior experience of participants and their responses.

While the general attitude toward the screening program is positive, most professionals feel the need to improve the current screening program by defining exclusion criteria, providing comprehensive pretest information and adding other BRCA1/2 founder mutations, as well as expanding the screening to include ethnicities other than Ashkenazi Jews.

Osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) facilitated by mechanical loading is a promising therapy for disuse osteoporosis (DOP), however, it is difficult to implement mechanical loading for a majority of patients. Our study aims to identify circ-ITCH-mediated novel approach to facilitate osteogenic differentiation in DOP.

A rat DOP model and human BM-MSCs under microgravity condition were generated as in vivo and in vitro models of DOP, respectively. The bone mineral density (BMD) and bone parameters were examined in rats. The histological changes of bones and mineralization were monitored by H&E, Alcian blue and Alizarin red S staining. Co-IP was employed to examine the ubiquitination of HOXC10 and the interaction between HOXC10 and BRCA1. The direct associations among circ-ITCH, IGFBP2 and BRCA1 mRNA were assessed by RIP, FISH and RNA pull-down assays.

Circ-ITCH was downregulated in rat model of DOP and BM-MSCs under microgravity stimulation. Circ-ITCH overexpression promoted osteogenic differentiation in BM-MSCs under microgravity condition. The altered bone parameters, such as BMD, trabecular number (Tb.N), trabecular separation (Tb.Sp), trabecular thickness (Tb.Th), and bone microstructure in DOP rats were rescued by circ-ITCH overexpression. Mechanistically, circ-ITCH enhanced the ubiquitination degradation of HOXC10 through enhancing BRCA1 mRNA stability. Circ-ITCH directly bound to IGF2BP2 protein to stabilize BRCA1 mRNA via m6A modification, thus facilitating osteogenic differentiation in BM-MSCs under microgravity condition.

Circ-ITCH stabilized BRCA1 mRNA via IGF2BP2-mediated m6A modification, thereby facilitating the ubiquitination degradation of HOXC10 to promote osteogenic differentiation in DOP.

This study mimics the metabolic environment of metabolic dysfunction-associated steatotic liver disease (MASLD) and diabetic mellitus (DM) to investigate the function of BRCA1 in regulating glucose and lipid metabolism in hepatocytes under high glucose (HG) settings.

MASLD and DM-related datasets (GSE89632, GSE95849) were screened for overlapping genes, Protein-Protein Interaction (PPI) network and enrichment analyses were performed. Then, quantitative real-time polymerase chain reaction (qRT-PCR), Western Blotting (WB), and enzymatic colorimetric assays to examine the expression changes of BRCA1 in mouse primary hepatocytes under HG conditions and the impact of the combined PI3K/Akt signaling pathway on key metabolic markers of gluconeogenesis and lipid metabolism.

Our study identified seven key overlapping genes (AURKA, BRCA1, ISG15, NUSAP1, OAS1, RSAD2, TLR7) between MASLD and DM. Experiments found that when BRCA1 was overexpressed in mouse primary hepatocytes, intracellular triglyceride content and lipid metabolism-related biomarkers (such as PEPCK, SREBP-1c, G6Pase, and FAS) were significantly increased in HG circumstances. However, the knockdown of BRCA1 reduced the expression of these indicators. Besides, we also observed that under HG conditions, the expression of proteins linked to the PI3K/Akt signaling pathway was negatively regulated by BRCA1 expression. Moreover, TG content and expression of lipid metabolism markers are also regulated by BRCA1 and PI3K/Akt pathway inhibitor Ly294002.

As a key regulator of hepatocyte metabolism under HG conditions, BRCA1 can participate in regulating glucose and lipid metabolism in mouse primary hepatocytes through the PI3K/AKT signaling pathway, which be able to become a possible remedy strategy for DM with MASLD.

Metabolic reprogramming is a hallmark of ovarian cancer, enabling tumor progression, immune evasion and drug resistance. The tumor microenvironment (TME) further shapes metabolic adaptations, enabling cancer cells to withstand hypoxia and nutrient deprivation. While organoid models provide a physiologically relevant platform for studying these processes, they still lack immune and vascular components, limiting their ability to fully recapitulate tumor metabolism and drug responses. In this study, we investigated the key metabolic mechanisms involved in ovarian cancer progression, focusing on glycolysis, lipid metabolism and amino acid metabolism. We integrated metabolomic analyses and drug sensitivity assays to explore metabolic-TME interactions using patient-derived, adult stem cell-derived and iPSC-derived organ tissues. Among these, we found that glycolysis, lipid metabolism and amino acid metabolism play a central role in tumor progression and chemotherapy resistance. We identified methylglyoxal (MGO)-mediated BRCA2 dysfunction as a driver of immune escape, a role for sphingolipid signaling in tumor proliferation and a role for kynurenine metabolism in CD8+ T cell suppression. In addition, PI3K/AKT/mTOR and Wnt/β-catenin pathways promote chemoresistance through metabolic adaptation. By elucidating the link between metabolic reprogramming and immune evasion, this study identifies key metabolic vulnerabilities and potential drug targets in ovarian cancer. Our findings support the development of metabolically targeted therapies and increase the utility of organoid-based precision medicine models.

Tumorigenesis in mammals is driven by inherited genetic variants, environmental factors and random errors during normal DNA replication that lead to cancer-causing mutations. These factors initiate uncontrolled cellular proliferation and disrupt the regulation of critical checkpoints. A few mammalian species possess unique protective mechanisms that enable them to resist widespread cancer development and achieve longevity. Tissue-specific tumor protection adds another layer of complexity to this diversity. Breast cancer is a leading cause of human mortality, particularly among females. Driven by the need for new strategies in treatment and prevention, this opinion article explores and supports the idea that herbivores are more resistant to mammary cancer than carnivores and omnivores. This diversity has occurred despite the remarkably similar basic mammary biology. Herbivores' meatless diet cannot explain the differences in cancer resistance, which have accompanied species segregation since the Jurassic era. To investigate the causes of this diversity, the characteristics of tumorigenesis in the human breast-and to a lesser extent in other carnivores-have been compared with data from retrospective analyses of bovine mammary tumor development across various locations over the past century. Well-established genomic, cellular, and systemic triggers of breast cancer exhibit different, or less pronounced tissue-specific activity in the bovine mammary gland, accompanied by novel bovine-specific protective mechanisms. Together, these factors contribute to the near absence of breast cancer in bovines and offer a basis for developing future anticancer strategies.

PARP inhibitors are a class of agents that have shown significant preclinical activity in models defective in homologous recombination (HR). The identification of synthetic lethality between HR defects and PARP inhibition led to several clinical trials in tumors with known HR defects (initially mutations in BRCA1/2 genes and subsequently in other genes involved in HR). These studies demonstrated significant responses in breast and ovarian cancers, which are known to have a significant proportion of patients with HR defects. Since the approval of the first PARP inhibitor (PARPi), olaparib, several other inhibitors have been developed, expanding the armamentarium available to clinicians in this setting. The positive results obtained in breast and ovarian cancer have expanded the use of PARPi in other solid tumors with HR defects, including prostate and pancreatic cancer in which these defects have been identified. The clinical trials have demonstrated responses to PARPi which are now also available for the subset of patients with prostate and pancreatic cancer with HR defects. This review summarizes the results obtained in solid tumors with PARPi and their potential use when combined with other agents, including immune checkpoint inhibitors that are likely to further increase the survival of these patients which still needs a dramatic improvement.

Mutations in the tumor suppressor genes BRCA1 and BRCA2 are associated with the triple-negative breast cancer phenotype, particularly aggressive and hard-to-treat tumors lacking estrogen, progesterone, and human epidermal growth factor receptor 2. This research aimed to understand the metabolic and genetic links behind BRCA1 and BRCA2 mutations and investigate their relationship with effective therapies. Using the Cytoscape software, two networks were generated through a bibliographic analysis of articles retrieved from the PubMed-NCBI database. We identified 98 genes deregulated by BRCA mutations, and 24 were modulated by therapies. In particular, BIRC5, SIRT1, MYC, EZH2, and CSN2 are influenced by BRCA1, while BCL2, BAX, and BRIP1 are influenced by BRCA2 mutation. Moreover, the study evaluated the efficacy of several promising therapies, targeting only BRCA1/BRCA2-mutated cells. In this context, CDDO-Imidazolide was shown to increase ROS levels and induce DNA damage. Similarly, resveratrol decreased the expression of the anti-apoptotic gene BIRC5 while it increased SIRT1 both in vitro and in vivo. Other specific drugs were found to induce apoptosis selectively in BRCA-mutated cells or block cell growth when the mutation occurs, i.e., 3-deazaneplanocin A, genistein or daidzein, and PARP inhibitors. Finally, over-representation analysis on the genes highlights ferroptosis and proteoglycan pathways as potential drug targets for more effective treatments.

We report a young female patient diagnosed with an invasive ductal carcinoma at the site of a prior cosmetic nipple piercing. She had no significant familial, genetic, or other carcinogenic risk factors to account for her presentation. A review of the literature confirms that trauma can occasionally be associated with invasive breast cancer, but such a connection has not previously been related to nipple piercing procedures.

The introduction of poly-ADP ribose polymerase (PARP) inhibitors (PARPi) has completely changed the treatment landscape of breast cancer susceptibility 1-2 (BRCA1-BRCA2)-mutant cancers and generated a new avenue of research in the fields of DNA damage response and cancer therapy. Despite this, primary and secondary resistances to PARPi have become a challenge in the clinic, and novel therapies are urgently needed to address this problem. After two decades of research, a unifying model explaining sensitivity of cancer cells to PARPi is still missing. Here, we review the current knowledge in the field and the increasing evidence pointing to a crucial role for replicative gaps in mediating sensitization to PARPi in BRCA-mutant and 'wild-type' cancer cells. Finally, we discuss the challenges to be addressed to further improve the utilization of PARPi and tackle the emergence of resistance in the clinical context.

Breast cancer (BC) remains a leading cause of cancer-related deaths among women globally, highlighting the urgent need for more effective and targeted therapies. Traditional treatments, including surgery, chemotherapy, and radiation, face limitations such as drug resistance, metastasis, and severe side effects. Recent advancements in gene therapy, particularly CRISPR/Cas9 technology and Oncolytic Virotherapy (OVT), are transforming the BC treatment landscape. CRISPR/Cas9 enables precise gene editing to correct mutations in oncogenes like HER2 and MYC, directly addressing tumor growth and immune evasion. Simultaneously, OVT leverages genetically engineered viruses to selectively destroy cancer cells and stimulate robust antitumor immune responses. Despite their potential, gene therapies face challenges, including off-target effects, delivery issues, and ethical concerns. Innovations in delivery systems, combination strategies, and integrating gene therapy with existing treatments offer promising solutions to overcome these barriers. Personalized medicine, guided by genomic profiling, further enhances treatment precision by identifying patient-specific mutations, such as BRCA1 and BRCA2, allowing for more tailored and effective interventions. As research progresses, the constructive interaction between gene therapy, immunotherapy, and traditional approaches is paving the way for groundbreaking advancements in BC care. Continued collaboration between researchers and clinicians is essential to translate these innovations into clinical practice, ultimately improving BC patients' survival rates and quality of life.

Bilateral risk-reducing mastectomy (BRRM) is the surgical removal of both breasts to reduce the risk of cancer. In this Society of Surgical Oncology position statement, we review the literature addressing the indications, outcomes, and risks of BRRM to update the society's 2017 statement. We held a virtual meeting to outline key topics and conducted a literature search using PubMed to identify relevant articles. After literature review, recommendations were made according to group consensus. Individuals with a high lifetime risk of breast cancer due to pathogenic variants in high penetrance breast cancer-predisposition genes, early chest or breast radiation exposure, or a compelling family history should be counseled on the option of BRRM. However, BRRM is not recommended for most patients with high-risk lesions and may be contraindicated in patients who have other competing cancers and/or a high risk of surgical complications. BRRM effectively reduces the risk of breast cancer development, although the survival benefit is unclear. For patients with low-to-moderate breast cancer risk, alternative management strategies should be encouraged, including lifestyle modifications, high-risk screening, and risk-reducing medications. Discussions of BRRM should cover: (1) breast-cancer risk estimates; (2) the procedure's degree of risk reduction and impact on survival; (3) surgical techniques, potential surgical complications and long-term sequelae; and (4) alternatives to surgery. Surgeons should encourage shared and informed decision making with patients who have an elevated lifetime risk of developing breast cancer.

Women with germline BRCA1/2 pathogenic variants (gBRCA1/2) are recommended to undergo annual breast MRI and mammography. Our objective was to describe the frequency of insurance denials for annual breast MRIs in women with gBRCA1/2 and determine denial trends.

Women with gBRCA1/2 following in a high-risk breast cancer clinic with breast MRIs ordered from 2020 to 2021 were identified and cross-referenced with a database of insurance denials. Radiology records were queried to determine if screening breast MRIs were performed in 2020 and 2021. Rates of MRI denials and outcomes after appeal were determined.

There were 682 women with gBRCA1/2 who had screening breast MRIs ordered from 2020 to 2021, including 318 (47 %) BRCA1, 356 (52 %) BRCA2, and 8 (1 %) with both. 73 women (11 %) had an MRI denied. Women insured through Medicaid had the highest rates of denials (2020: 7 %, 2021: 18 %), followed by commercial insurance (2020: 6 %, 2021: 9 %). There were significantly more denials in 2021 compared to 2020 (p = 0.044), and 2021 denials were more likely to be denied on appeal. Of women with denials, 4 (14 %) in 2020 and 5 (11 %) in 2021 did not have a screening MRI performed. One patient with DCIS had an MRI denial prior to diagnosis.

Breast MRI insurance denials were present in 11 % of this high-risk cohort, and 14 % of women with denials did not undergo annual screening. There were significantly more denials in 2021, suggesting worsening barriers for these patients and added burden on providers to appeal for appropriate screening tests.

The NHS Jewish BRCA Testing Programme is offering germline BRCA1 and BRCA2 genetic testing to people with ≥1 Jewish grandparent. Who have an increased likelihood of having an Ashkenazi Jewish (AJ) founder germline pathogenic variant (gPV) compared with the general population.Testing is offered via a self-referral, home-based saliva sampling pathway, supported by a genetic counsellor telephone helpline. A first-of-its-kind in the United Kingdom (UK) for population genetic testing, outside of research.

We reviewed data from germline testing of 5389 people who registered during the soft-launch phase (January 2023-January 2024) and their families to observe trends in uptake and outcomes of testing.

Of the 5389 self-referrals, 4339 (80.5%) consented to testing. Of those with results returned, 2.3% (98/4,274) had a gPV (89.8% AJ founder and 10.2% non-AJ founder).Notably, the detection rate was higher in men (42/790, 5.3%) compared with women (56/3484, 1.6%), with the proportion reporting known BRCA variants within the family prior to consent also significantly increased (13.1% compared with 9.2%, respectively).

Overall detection rates of gPVs are similar to those reported elsewhere from Jewish population testing. The pathway, particularly for males, may attract uptake of testing by those previously aware of familial gPVs.

Osteoprotegerin (OPG), encoded by the TNFRSF11B gene, is linked to the development of breast cancer via several pathways, including interactions with the receptor activator of nuclear factor-κB (RANK) ligands, apoptosis-inducing proteins like TRAIL, and genetic variations such as single nucleotide polymorphisms (SNPs), directly altering gene expression. This review aims to investigate the role of OPG expression in breast cancer.

A comprehensive literature search was conducted using PubMed Medline, Google Scholar, and ScienceDirect. Only full-text English publications from inception to September 2024 were included.

Studies have demonstrated that certain SNPs in the OPG gene, specifically rs3102735 and rs2073618, are linked to a higher risk of breast cancer development. Additionally, OPG's function as a TRAIL decoy receptor may inhibit the death of cancer cells. Furthermore, OPG in the serum and its interactions with BRCA mutations are being investigated for their potential influence on breast cancer progression. Studies have found that OPG promotes tumorigenesis by enhancing cell proliferation, angiogenesis, and aneuploidy in normal mammary epithelial cells. Moreover, OPG mediates the tumor-promoting effects of interleukin-1 beta and may serve as a biomarker for breast cancer risk, particularly in BRCA1 mutation carriers, through its role in dysregulated RANK signaling. Lastly, the use of recombinant OPG in mouse models has been found to exert anti-tumor effects.

In this review, the role of OPG in breast cancer is examined. OPG has a multifaceted role in breast cancer tumorigenesis and exerts its effects through genetic variations (SNPs), interactions with TNF-related apoptosis-inducing ligand (TRAIL), and the modulation of the pro-tumorigenic microenvironment effects of angiogenesis, cell survival, and metastasis. Additionally, OPG's dual role as a tumor suppressor and promoter serves as a possible therapeutic target to enhance apoptosis, limit bone metastasis, and modulate the tumor microenvironment. Whilst much is now known, further studies are necessary to fully delineate the role of OPG.

Drug repositioning, the practice of identifying novel applications for existing drugs beyond their originally intended medical indications, stands as a transformative strategy revolutionizing pharmaceutical productivity. In contrast to conventional drug development approaches, this innovative method has proven to be exceptionally effective. This is particularly relevant for cancer therapy, where the demand for groundbreaking treatments continues to grow. This review focuses on drug repositioning for ovarian cancer treatment, showcasing a comprehensive exploration grounded in thorough in vitro experiments across diverse cancer cell lines, which are validated through preclinical in vivo models. These insights not only shed light on the efficacy of these drugs but also expand in potential synergies with other pharmaceutical agents, favoring the development of cost-effective treatments for cancer patients.

The single nucleotide polymorphism in NOD2 (rs2066847) is associated with conditions that may predispose to the development of gastrointestinal disorders, as well as the known BRCA1 and BRCA2 variants classified as risk factors in many cancers. In our study, we analyzed these variants in a group of patients with pancreatitis and pancreatic cancer to clarify their role in pancreatic disease development. The DNA was isolated from whole blood samples of 553 patients with pancreatitis, 83 patients with pancreatic cancer, 44 cases of other pancreatic diseases, and 116 healthy volunteers. The NOD2 (rs2066847), BRCA1 (rs80357914) and BRCA2 (rs276174813) were genotyped. The statistically significant 3-fold increased risk of pancreatic cancer was detected among the patients with rs2066847 polymorphism (OR = 2.77, p-value = 0.019). We did not find the studied polymorphisms in BRCA1 (rs80357914) and BRCA2 (rs276174813). However, the adjacent polymorphisms have been detected only in patients with pancreatic diseases. The studied variant in NOD2 occurs more frequently in pancreatic patients and significantly increases the risk of pancreatic cancer. It can be considered as a genetic risk factor that predisposes to cancer development. The analyzed regions in BRCA1 and BRCA2 may be a potential target in further search for a genetic marker of pancreatic diseases.

Breast cancer incidence is increasing in women under age 40, underscoring the need for research on breast cancer risk factors for younger women.

We used data from an international family cohort (n = 26,348) to examine whether recreational physical activity (RPA) during adolescence and early adulthood is associated with breast cancer risk before age 40. The cohort includes 2,502 women diagnosed with breast cancer before age 40, including 2,408 diagnosed before study enrollment (68% within 5 years of enrollment). Women reported their average hours per week of moderate and strenuous RPA during adolescence (12-17 years) and early adulthood (25-34 years), which were converted to total age-adjusted metabolic equivalents per week and categorized into quartiles. We conducted attained age analyses until age 40 (follow-up time began at age 18) using Cox proportional hazards regression models adjusted for study center, race and ethnicity, and education.

Being in the highest versus lowest quartile of RPA during adolescence and early adulthood were respectively associated with 12% [HR (95% confidence interval, or CI), 0.88 (0.78-0.98)] and 16% [HR (95% CI), 0.84 (0.74-0.95) lower breast cancer risks before age 40. Being in the highest quartile of RPA during both adolescence and early adulthood (Pearson correlation = 0.52) versus neither time point was associated with a 22% lower risk [HR (95% CI), 0.78 (0.68-0.89)].

Findings suggest that RPA during adolescence and early adulthood may lower breast cancer risk before age 40.

Policies promoting physical activity during adolescence and early adulthood may be important for reducing the growing burden of breast cancer in younger women.

Massively parallel sequencing technologies have been a boon to many fields of biological science, including oncology. Cancer is an umbrella term for many diseases featuring abnormal cellular growth due to genetic and epigenetic aberrations. Advances in sequencing technology allow for interrogation of the DNA and RNA of cancer cells and other cells in the tumor microenvironment down to a single-base resolution. However, these strides come after a rich history of ground-breaking biological assays, like the discovery of the Philadelphia chromosome in the context of leukemia. Many specific genetic and epigenetic modifications have been implicated in oncogenesis, cancer progression, and response to treatment. Sequencing technologies have also helped to associate populations of bacteria in the microbiome to cancer development and prognosis. However, all this new information, especially when procured via high-throughput methods, comes at the cost of being more computationally and staff-resource intensive. There is also more risk to the privacy of the individuals with sequenced genomes. Notwithstanding, the overall benefit of sequencing technologies can greatly outweigh the risks with careful advancements and continued focus on the goal: helping those affected by cancer via precision medicine. Cancer biology has been and will continue to be elucidated by sequencing innovations in ways unimaginable without it.

Women with germline BRCA1 mutations face an increased risk of developing breast and ovarian cancers. BARD1 (BRCA1 associated RING domain 1) is an essential heterodimeric partner of BRCA1, and mutations in BARD1 are also associated with these cancers. While BARD1 mutations are recognized for their cancer susceptibility, the exact roles of numerous BARD1 missense mutations remain unclear. In this study, we conducted functional assays to assess the homology-directed DNA repair (HDR) activity of all BARD1 missense substitutions identified in 55 breast and ovarian cancer samples, using the real-world data from the COSMIC and cBioPortal databases. Seven BARD1 variants (V85M, P187A, G491R, R565C, P669L, T719R, and Q730L) were confirmed to impair DNA damage repair. Furthermore, cells harboring these BARD1 variants exhibited increased sensitivity to the chemotherapeutic drugs, cisplatin, and olaparib, compared to cells expressing wild-type BARD1. These findings collectively suggest that these seven missense BARD1 variants are likely pathogenic and may respond well to cisplatin-olaparib combination therapy. This study not only enhances our understanding of BARD1's role in DNA damage repair but also offers valuable insights into predicting therapy responses in patients with specific BARD1 missense mutations.

Poly (ADP-ribose) polymerase 1 (PARP1) catalyzes poly (ADP) ribosylation reaction, one of the essential post-translational modifications of proteins in eukaryotic cells. Given that PARP1 inhibition can lead to synthetic lethality in cells with compromised homologous recombination, this enzyme has been identified as a potent target for anti-cancer therapeutics. However, the clinical application of existing PARP1 inhibitors is restrained by side effects associated with DNA trapping and off-target effects, highlighting the need for improved therapeutic strategies. By integrating protein degradation technology, we synthesized a PROTAC molecule 180055 based on the Rucaparib junction and VHL ligand, which efficiently and selectively degraded PARP1 and inhibited PARP1 enzyme activity without a noticeable DNA trapping effect. Furthermore, 180055 kills tumor cells carrying BRCA mutations with a minor impact on the growth of normal cells both in vitro and in vivo. This suggests that 180055 is a PARP1-degrading compound with excellent pharmacological efficacy and extremely high biological safety that deserves further exploration and validation in clinical trials.

The combined effect of cardiovascular risk factors on breast cancer in women is unknown. The relationship between genetic risk combined with cardiovascular health (CVH) levels and breast cancer has not been confirmed. This study aims to explore the relationship between CVH level based on life's essential 8 (LE8) score and breast cancer risk in women with different menopausal statuses and to estimate further the effect of CVH level combined with genetic susceptibility on breast cancer risk. A total of 118,911 women from UK Biobank were included in the study, including 22,676 premenopausal women and 96,235 postmenopausal women. The association between the CVH level and the risk of breast cancer in women with different menopausal statuses was assessed using the Cox proportional hazards regression models, with the healthiest CVH group as the reference. In addition, risk ratios (HRs) and 95% confidence intervals (95% CIs) for the joint effect of the CVH level and polygenic risk score (PRS) were calculated using the PRS from the UK Biobank. During a mean follow-up period of 13.8 years, we observed 733 cases and 3,645 cases of breast cancer in premenopausal and postmenopausal women, respectively. In premenopausal women, the risk of breast cancer was significantly increased in the intermediate CVH group (HR, 1.28; 95%CI 1.08-1.52) and the low CVH group (HR, 1.44; 95%CI 1.13-1.85). In postmenopausal women, the risk of incidence was also significantly increased in the intermediate CVH group (HR, 1.20; 95%CI 1.07-1.32) and the low CVH group (HR, 1.34; 95%CI 1.17-1.54). In the joint effect analysis, the risk of breast cancer for women in the low CVH group and the high genetic risk group was highest in both premenopausal (HR, 8.26; 95%CI 4.44-15.35) and postmenopausal (HR, 8.10; 95%CI 5.50-11.93) women. Women with lower LE8 scores and higher genetic susceptibility have the higher risk of breast cancer. This suggests that women with lower levels of CVH and higher genetic susceptibility have an increased risk of breast cancer under different menopausal statuses.

Breast cancer dominates women's mortality, and among other factors, mutations in the BRCA1 gene are significant risk factors. Several approaches are followed to treat the BRCA1 affected cancer patients. However, specific BRCA1 inhibitors are not available till date due to its structural complexity. In addition, there are several limitations associated with the existing drugs used to treat BRCA1-related breast cancer and some side effects. The side effects include symptoms such as hot flashes, joint pain, nausea, fatigue, hair loss, diarrhea, chills, fever, and others. Therefore, advanced approaches needed that can overcome all the limitations and side effects of the current inhibitors. In this study, we adopted a multistep approach to identify potential inhibitors for BRCA1-mutated breast cancer. We used our developed machine learning models to screen potential inhibitors. Molecular docking approach was carried out for the screened hit compounds with BRCA1 and its mutated forms. Two ligands, β-amyrin and Narirutin, has shown significant performance in multiple scoring schemes such as molecular docking and RF score calculations. Molecular dynamics simulations demonstrated the stability of the complexes formed by β-amyrin and Narirutin with BRCA1, with lower RMSD values and less RMSF fluctuations at the binding site locations. Principal component analysis (PCA) and free energy landscape (FEL) further confirmed the compactness and favorable binding of β-Amyrin and Narirutin to BRCA1. These findings suggest that β-amyrin and Narirutin have potential as therapeutic agents against BRCA1-mutated breast cancer.

The utilization of PARP inhibitors (PARPis) has significantly improved the prognosis for ovarian cancer patients. However, as the use of PARPis increases, the issue of PARPi resistance has become more prominent. Prolonged usage of PARPis can lead to the development of resistance in ovarian cancer, often mediated by mechanisms such as homologous recombination (HR) recovery, ultimately resulting in cancer relapse. Overcoming PARPi resistance in ovarian cancer is a pressing concern, aiming to enhance the clinical benefits of PARPi treatment and delay disease recurrence. Here, we summarize the mechanisms underlying PARPi resistance, methods for analyzing resistance, and strategies for overcoming it. Our goal is to inspire the development of more cost-effective and convenient methods for analyzing resistance mechanisms, as well as safer and more effective strategies to overcome resistance. These advancements can contribute to developing personalized approaches for treating ovarian cancer.

High-grade serous ovarian cancer (HGSOC) represents the most lethal subtype of ovarian cancer, largely due to being commonly diagnosed at advanced stages. The early molecular mechanisms underlying ovarian carcinogenesis remain poorly defined, posing challenges to the development of prevention and early detection strategies. Here we dissect the molecular mechanisms of sex steroid hormone signaling throughout the decades-long evolution of HGSOC precursor lesions, which predominantly originate from secretory epithelial cells of fallopian tubes (FT). We also discuss the prognostic significance of sex steroid receptor isoforms and steroid metabolizing enzymes in HGSOCs. Finally, we provide a comprehensive gene expression atlases of sex steroid receptors, steroidogenic, and steroid-metabolizing enzymes across different cell populations in pre- and postmenopausal FTs, and HGSOCs, using published single-cell RNA sequencing datasets. These atlases reveal that secretory epithelial cells and stromal populations in FTs express sex steroid receptors and enzymes responsible for the formation and inactivation of genotoxic estrogen metabolites. In HGSOC, epithelial cells express various HSD17B isoforms and steroid conjugating enzymes, suggesting an enhanced ability to finely regulate the levels of bioactive sex steroids.

Different types of mastectomies leave different amounts of residual breast tissue. The significance of the residual breast volume (RBV) is not clear. Therefore, we developed an MRI tool that allows to easily assess the RBV. In this study we evaluated factors associated with RBV after skin or nipple sparing mastectomy (SSM/NSM) in breast cancer BRCA pathogenic variant (PV) carriers who underwent both therapeutic and risk reducing SSM/NSM and its relation to breast cancer outcomes using an innovative MRI-based tool.

Data of breast cancer BRCA PV who were treated between 2006 and 2020 were retrieved from of the oncogenetics unit databases. Only patients who underwent SSM/NSM and had a postoperative breast MRI available for analysis were included. Data collected included demographics, clinicopathological features, and outcomes. The MRI tool was developed by a breast cancer imaging laboratory. A logistic regression test and 95% confidence interval (CI) were used to assess the associated risk of increased RBV. A forward stepwise linear regression was used to correlate tumour-patient specific factors and RBV, and a Kaplan-Meier curve to show the probability of locoregional relapse.

A total of 84 patients undergoing 89 mastectomies were included. At a median follow-up of 98 months, 5 local, 2 regional, and 4 distant recurrences were observed. RBV was not significantly related with breast cancer outcomes (p value = NS). A higher body mass index (BMI) was associated with a higher RBV (p < 0.0001). A larger number of involved axillary nodes was associated with a smaller RBV (p = 0.025). The RBV on the risk-reducing mastectomy side was significantly higher compared to the breast cancer side (p value = 0.007). Local recurrences occurred in the vicinity of the primary tumour.

Cancer represents a major global public health burden, with new cases estimated to increase from 14 million in 2012 to 24 million by 2035. Primary prevention is an effective strategy to reduce the costs associated with cancer burden. For example, measures to ban tobacco consumption have dramatically decreased lung cancer incidence and vaccination against human papillomavirus can prevent cervical cancer development. Unfortunately, the etiological factors of many cancer types are not completely clear or are difficult to actively control; therefore, the primary prevention of such cancers is not practical. In this review, we update the progress on precision therapy by targeting the whole carcinogenesis process, especially for three high-risk groups: (1) those with chronic inflammation, (2) those with inherited germline mutations, and (3) those with precancerous lesions like polyps, gastritis, actinic keratosis or dysplasia. We believe that attenuating chronic inflammation, treating precancerous lesions, and removing high-risk tissues harboring germline mutations are precision methods for cancer prevention.

Undifferentiated embryonal sarcoma of the liver is a rare mesenchymal malignancy that predominantly occurs in children. The relationship between this tumor entity and germline pathogenic variants (PVs) remains undefined. Here, we present the clinical case of a male patient diagnosed with undifferentiated embryonal sarcoma of the liver. Both germline and tumor samples were analyzed using next-generation sequencing. In the tumor tissue, PVs in TP53 (NM_000546.5):c.532del p.(His178Thrfs*69) and CHEK2 (NM_007194.4):c.85C>T p.(Gln29*) were identified, with both confirmed to be of germline origin. Copy number analyses indicated a loss of the wildtype TP53 allele in the tumor, consistent with a second hit, while it was the variant CHEK2 allele that was lost in the tumor. Our data indicate that the germline TP53 PV acts as a driver of tumorigenesis in the reported case and support a complex interaction between the germline TP53 and CHEK2 PVs. This case highlights the dynamic interplays of genetic alterations in tumorigenesis and emphasizes the need for continued investigation into the complex interactions between TP53 and CHEK2 PVs and into the association of undifferentiated embryonal sarcoma of the liver and Li-Fraumeni syndrome.

Breast cancer is a highly complex disease with multiple subtypes. While many of the breast cancer cases are sporadic some can be familial or hereditary. Genomic integrity is closely monitored by several mechanisms, such as DNA damage machinery and mitotic checkpoints. Any defect in the key genes involved in the regulation of these mechanisms often results in genomic instability, predisposing the cells to malignancy. This results in altered expression of many coding and noncoding genes. The noncoding RNAs especially the long noncoding RNA (lncRNAs) and microRNA (miRNAs) act as key regulators of cancer gene networks. Some miRNAs repress the expression of the heterochromatin-associated proteins, inducing the formation of open chromatin, and promoting the expression of genes required for oncogenesis. Additionally, specific miRNAs may also favour cancer progression and metastasis by regulating the expression of genes that support the metabolic microenvironment essential for cancer cell growth and proliferation. Understanding how these noncoding RNAs contribute to breast cancer development opens potential avenues for therapeutic intervention, targeting their dysregulated activity.

In the Emilia-Romagna region of Italy, a unique Hub and Spoke model was adopted to recognize BRCA-related breast cancer (BC) patients. Characteristics and outcomes of tumors identified by this model will be presented.

This multicenter retrospective cohort study involved patients diagnosed with BRCA-related BC identified in the Emilia-Romagna region between January 2000 and December 2013. Seven provinces collected data on patient and tumor characteristics; clinical and gene testing information were also registered. Comparisons between BRCA1 and BRCA2 BC were performed. To balance different variants to identify significant predictors of survival, an inverse probability of treatment weighting (IPTW) analysis on Cox regression was conducted.

From 2000 to 2013, 284 BRCA-related BC were registered (171 BRCA1, 110 BRCA2, and 3 BRCA1 and BRCA2). BRCA1 were diagnosed at an earlier stage compared to BRCA2 (50.1 % vs 30 %, respectively, in stage I, P = 0.0015). BRCA2 patients underwent more up-front surgery (85 % vs. 74.9 %, P = 0.049) and less chemotherapy (69.1 % vs 88.9 %, P = 0.004) than BRCA1 patients. At 11.8 years median follow-up, BRCA1 patients developed more second contralateral BC (P = 0.09), while BRCA2 had more visceral relapses (P = 0.013). No differences in overall survival (OS) between BRCA1 and BRCA2 patients (P = 0.07) were found. An advantage in OS was independently seen for patients who underwent contralateral prophylactic mastectomy (P = 0.0001) and oophorectomy (P < 0.0001).

In conclusion, adopting a homogeneous regional framework provides important information about prevention and treatment strategies of BRCA-related BC and suggests using maximal surgery to improve OS.

A hereditary component of breast (BC) and colorectal cancer (CRC) has been described in approximately one-third of these tumor types. BC patients have an increased risk of developing CRC as a second primary tumor and vice versa. Germline genomic variants (NextSeq550, Illumina) were investigated in 24 unrelated BC and/or CRC patients and 7 relatives from 3 index patients. Fifty-six pathogenic or likely pathogenic variants were identified in 19 of 24 patients. We detected single-nucleotide variants (SNVs) in CRC predisposition genes (MLH1 and MUTYH) and other promising candidates (CDK5RAP3, MAD1L1, NOS3, and POLM). Eighteen patients presented SNVs or copy number variants (CNVs) in DNA damage repair genes. We also identified SNVs recently associated with BC or CRC predisposition (PABPC1, TYRO3, MAP3K1, SLC15A4, and LAMA1). The PABPC1c.1255C>T variant was detected in nine unrelated patients. Each patient presented at least one SNV/CNV in a candidate gene, and most had alterations in more than one gene, reinforcing a polygenic model for BC/CRC predisposition. A significant fraction of BC/CRC patients with a family history of these tumors harbored deleterious germline variants in DNA repair genes. Our findings can lead to strategies to improve the diagnosis, genetic counseling, and treatment of patients and their relatives.

Examine decision-making regarding when women would prefer to receive reproductive carrier and cancer predisposition screening and from what clinician.

20 women completed in-depth interviews via Zoom exploring their views on the provision of reproductive carrier and cancer predisposition screening. Our analysis identified themes related to what informs women's preferences for when they would like to receive a genetic screening offer and by which clinician.

Participants' responses to questions about when they would be interested in receiving genetic screening were best understood through the lens of the Extended Parallel Process Model. Specifically, personal utility of the information, a woman's family health history and cost were key factors in decision-making. Women considered their clinician's knowledge and their trust in and relationship with the clinician when deciding from whom they would prefer to receive an offer of genetic screening.

OB/GYN clinic patients may accept an offer of genetic screening from a knowledgeable and trusted clinician for carrier and cancer predisposition screening preconceptionally or prenatally.

Integrating genetic reproductive and cancer predisposition screening into the care provided to reproductive age OB/GYN patients may be acceptable to this population.

In the current study, we have investigated the secondary metabolites present in ethnomedical plants used for medicinal purposes-Astilbe chinensis (EK1), Scutellaria barbata D. Don (EK2), Uncaria rhynchophylla (EK3), Fallugia paradoxa (EK4), and Curcuma zedoaria (Christm.) Thread (EK5)-and we have compared them with five compounds of synthetic origin for the inhibition of PARP-1, which is linked to abnormal DNA replication, generating carcinogenic cells. We have studied these interactions through molecular dynamics simulations of each interacting system under physiological conditions (pH, temperature, and pressure) and determined that the compounds of natural origin have a capacity to inhibit PARP-1 (Poly(ADP-ribose) Polymerase 1) in all the cases inspected in this investigation. However, it is essential to mention that their interaction energy is relatively lower compared to that of compounds of synthetic origin. Given that binding energy is mandatory for the generation of a scale or classification of which is the best interacting agent, we can say that we assume that compounds of natural origin, having a complexation affinity with PARP-1, induce cell apoptosis, a potential route for the prevention of the proliferation of carcinogenic cells.

Fear of cancer recurrence (FCR) affects virtually all patients who have been treated for cancer, to varying degrees. Breast cancer survivors who carry a BRCA1 or BRCA2 gene mutation are at high risk of cancer recurrence. No study has yet assessed FCR specifically in this population.

This cross-sectional study, conducted in women who were treated for breast cancer and carrying a BRCA1/2 mutation, aimed to: (1) assess the mean level of FCR and estimate the proportion of patients with clinical levels of FCR; (2) examine the relationships between FCR and selected psychological variables (e.g., avoidance, intolerance to uncertainty) and quality of life; (3) explore whether FCR levels vary as a function of the past preventive treatment received; and (4) to assess the associations between FCR and the presence of decisional conflict or regret regarding the various preventive options.

Participants were recruited through an e-mail sent to an oncogenetic network mailing list (Réseau ROSE). Participants were asked to complete a battery of questionnaires online assessing FCR and other psychological and quality of life variables.

A total of 89 women completed the survey. Most participants had undergone a preventive mastectomy (62.9%) and a preventive salpingo-oophorectomy (75.3%) at the time of the study. The mean Fear of Cancer Recurrence Inventory-severity score was 16.8, which exceeds the clinical cut-off score of 13, and 70.8% of the participants showed a clinical level of FCR. FCR was significantly associated with higher levels of anxiety and depression, and higher avoidance and intolerance of uncertainty, but not with quality of life. No significant difference was observed on the total FCR score between women who had received preventive surgery (mastectomy and/or salpingo-oophorectomy) and those considering it, and those not considering it. The association was significant between higher FRC scores and greater decisional conflicts and regrets about choosing to undergo preventive surgery.

These data suggest that FCR is a significant problem for breast cancer survivors carrying a BRCA1/2 genetic mutation, even after undergoing a prophylactic surgery. This highlights the importance of providing these women with specific psychological intervention focusing on FCR.

Breast cancer is reported to be one of the most lethal cancers in women, and its multi-target detection can help improve the accuracy of diagnosis. In this work, a cluster regularly interspaced short palindromic repeats (CRISPR)-Cas13a/Cas12a-based system was established for the simultaneous fluorescence detection of breast cancer biomarkers circROBO1 and BRCA1. CRISPR-Cas13a and CRISPR-Cas12a were directly activated by their respective targets, resulting in the cleavage of short RNA and DNA reporters, respectively, thus the signals of 6-carboxyfluorescein (FAM) and 6-carboxy-xrhodamine (ROX) were restored. As the fluorescence intensities of FAM and ROX were dependent on the concentrations of circROBO1 and BRCA1, respectively, synchronous fluorescence scanning could achieve one-step detection of circROBO1 and BRCA1 with detection limits of 0.013 pM and 0.26 pM, respectively. The system was highly sensitive and specific, holding high diagnostic potential for the detection of clinical samples. Furthermore, the competing endogenous RNA mechanism between circROBO1 and BRCA1 was also explored, providing a reliable basis for the intrinsic regulatory mechanism of breast cancer.