Comprehensive breast cancer risk analysis with whole exome sequencing and the prevalence of BRCA1 and ABCG2 mutations and oncogenic HPV.

Breast cancer is the most prevalent cancer and also the leading cause of cancer death in women worldwide. A comprehensive understanding of breast cancer risk factors and their incidences is useful information for breast cancer prevention and control planning. The present study aimed to provide information on single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) in breast cancer, the allele frequency of two SNPs in breast cancer-related genes BRCA1 DNA repair associated (BRCA1; rs799917) and ATP binding cassette subfamily G member 2 (ABCG2; rs2231142), and the prevalence of human papillomavirus (HPV) infections in a normal population living in Phayao Province, Northern Thailand. One breast cancer and 10 healthy samples were investigated by whole exome sequencing (WES) and compared for genetic variation. The WES data contained SNPs in genes previously implicated in breast cancer and provided data on CNVs. The allele frequencies for SNPs rs799917 and rs2231142 were also examined. The SNP genotype frequencies were 35.88% CC, 46.54% CT, and 17.58% TT for rs799917 and 33.20% CC, 46.88% CA, and 19.92% AA for rs2231142. A total of 825 human whole blood samples were examined for HPV infection by PCR, and the pooled DNA was tested for HPV infection using metagenomic sequencing. No HPV infections were detected among all 825 samples or the pooled blood samples. The incidence of breast cancer among the tested samples was estimated based on acceptable breast cancer risk factors and demographic data and was 1.47%. The present study provided data on SNPs and CNVs in breast cancer-related genes. The associations between SNPs rs2231142 and rs799917 and breast cancer should be further investigated in a case-control study since heterozygous and homozygous variants are more common. Based on the detection of HPV infection in the blood samples, HPV may not be associated with breast cancer, at least in the Northern Thai population.

DOT1L-mediated RAP80 methylation promotes BRCA1 recruitment to elicit DNA repair.

Breast Cancer Type 1 Susceptibility Protein (BRCA1) is a tumor-suppressor protein that regulates various cellular pathways, including those that are essential for preserving genome stability. One essential mechanism involves a BRCA1-A complex that is recruited to double-strand breaks (DSBs) by RAP80 before initiating DNA damage repair (DDR). How RAP80 itself is recruited to DNA damage sites, however, is unclear. Here, we demonstrate an intrinsic correlation between a methyltransferase DOT1L-mediated RAP80 methylation and BRCA1-A complex chromatin recruitment that occurs during cancer cell radiotherapy resistance. Mechanistically, DOT1L is quickly recruited onto chromatin and methylates RAP80 at multiple lysines in response to DNA damage. Methylated RAP80 is then indispensable for binding to ubiquitinated H2A and subsequently triggering BRCA1-A complex recruitment onto DSBs. Importantly, DOT1L-catalyzed RAP80 methylation and recruitment of BRCA1 have clinical relevance, as inhibition of DOT1L or RAP80 methylation seems to enhance the radiosensitivity of cancer cells both in vivo and in vitro. These data reveal a crucial role for DOT1L in DDR through initiating recruitment of RAP80 and BRCA1 onto chromatin and underscore a therapeutic strategy based on targeting DOT1L to overcome tumor radiotherapy resistance.

Streamlined Genetic Education and Cascade Testing in Men from Hereditary Breast Ovarian Cancer Families: A Randomized Trial.

INTRODUCTION: When a pathogenic BRCA1 or BRCA2 mutation is identified in a family, cascade genetic testing of family members is recommended since the results may inform screening or treatment decisions in men and women. However, rates of cascade testing are low, and men are considerably less likely than women to pursue cascade testing. To facilitate cascade testing in men, we designed a Web-based genetic education tool that addressed barriers to cascade testing, was individually tailored, delivered proactively, and could be used in lieu of pretest genetic counseling to streamline the cascade testing process. METHODS: We randomized 63 untested men from hereditary cancer families to Web-based genetic education (WGE) versus enhanced usual care (EUC). WGE participants were provided access to a genetic education website after which they could accept or decline genetic testing or opt for pretest genetic counseling. EUC participants received an informational brochure and a letter informing them of their eligibility for genetic testing and recommending they schedule genetic counseling. The primary outcome was the uptake of genetic testing. RESULTS: Men in the WGE group were more likely to complete genetic counseling and/or genetic testing (43% vs. 12.1%; χ2 [n = 63, df = 1] = 7.77, p = 0.005). WGE participants were also more likely to complete genetic testing compared to men in the EUC group (30% vs. 9.1%; χ2 [n = 63, df = 1] = 4.46, p = 0.03). CONCLUSION: This preliminary trial suggests that a streamlined approach to genetic testing using proactively delivered genetic education may reduce barriers to cascade testing for at-risk men, leading to increased uptake. These results should be interpreted cautiously given the select sample and high rate of non-response.

Case Report of Complete Response to Olaparib in a Patient with Breast Cancer Brain Metastases.

Introduction: Breast cancer is the second most common cause of central nervous system (CNS) metastases. It has been shown that the median time from breast cancer diagnosis to CNS metastasis is 30.9 months and that the overall median survival after metastasis is extremely poor at 6.8 months. Although treatment options for ErbB2 Receptor Tyrosine Kinase 2 (ERBB2)-positive breast cancer brain metastasis (BCBM) have been reported, effective treatment options for ERBB2-negative BCBM, which has one of the worst prognoses, are limited. Olaparib is one of the standard treatments for germline BRCA1/2 mutated (gBRCA1/2mt), ERBB2-negative, metastatic, or recurrent breast cancer. However, there is minimal existing evidence to evaluate the efficacy of olaparib in BCBM. Case Presentation: In our report, we assessed the case of a Japanese woman in her early 30s, ERBB2-negative, gBRAC2mt-positive BCBM, who achieved a complete response and prolonged progression-free survival of 9 months after the initiation of treatment with olaparib. Conclusions: Thus, our case report demonstrated the significant efficacy of olaparib in BCBM treatment. Furthermore, we highlighted the need for more studies to investigate the efficacy of olaparib and explore the efficacy of poly ADP ribose polymerase inhibitors in BCBM.

Synergistic antitumor effect of liposomal-based formulations of olaparib and topotecan in primary epithelial ovarian cancer cells.

BACKGROUND: Olaparib is a PARP inhibitor inducing synthetic lethality in tumors with deficient homologous recombination (HRD) caused by BRCA1/2 mutations. The FDA has approved monotherapy for first-line platinum-sensitive, recurrent high-grade epithelial ovarian cancer. Combination therapy alongside DNA-damaging therapeutics is a promising solution to overcome the limited efficacy in patients with HRD. The present study was designed to develop topotecan- and olaparib-loaded liposomes (TLL and OLL) and assess the effectiveness of their combination in patient-derived ovarian cancer samples. METHODS: We used HEOC, four clear-cell tumors (EOC 1-4), malignant ascites, and an OCI-E1p endometrioid primary ovarian cancer cell line and performed NGS analysis of BRCA1/2 mutation status. Antiproliferative activity was determined with the MTT assay. The Chou-Talalay algorithm was used to investigate the in vitro pharmacodynamic interactions of TLLs and OLLs. RESULTS: The OLL showed significantly higher efficacy in all ovarian cancer types with wild-type BRCA1/2 than a conventional formulation, suggesting potential for increased in vivo efficacy. The TLL revealed substantially higher toxicity to EOC 1, EOC 3, ascites and lower toxicity to HEOC than the standard formulation, suggesting better therapeutic efficacy and safety profile. The combination of studied compounds showed a higher reduction in cell viability than drugs used individually, demonstrating a synergistic antitumor effect at most of the selected concentrations. CONCLUSIONS: The concentration-dependent response of different ovarian cancer cell types to combination therapy confirms the need for in vitro optimization to maximize drug cytotoxicity. The OLL and TLL combination is a promising formulation for further animal studies, especially for eliminating epithelial ovarian cancer with wild-type BRCA1/2.

Prognostic prediction and immune checkpoint profiling in glioma patients through neddylation-associated features.

BACKGROUND: Gliomas are the most common primary malignant tumours of the central nervous system, and neddylation may be a potential target for the treatment of gliomas. Our study analysed neddylation's potential role in gliomas of different pathological types and its correlation with immunotherapy. METHODS: Genes required for model construction were sourced from existing literature, and their expression data were extracted from the TCGA and CGGA databases. LASSO regression was employed to identify genes associated with the prognosis of glioma patients in TCGA and to establish a clinical prognostic model. Biological changes in glioma cell lines following intervention with hub genes were evaluated using the CCK-8 assay and transwell assay. The genes implicated in the model construction were validated across various cell lines using Western blot. We conducted analyses to examine correlations between model scores and clinical data, tumor microenvironments, and immune checkpoints. Furthermore, we investigated potential differences in molecular functions and mechanisms among different groups. RESULTS: We identified 249 genes from the Reactome database and analysed their expression profiles in the TCGA and CGGA databases. After using LASSO-Cox, four genes (BRCA1, BIRC5, FBXL16 and KLHL25, p < 0.05) with significant correlations were identified. We selected FBXL16 for validation in in vitro experiments. Following FBXL16 overexpression, the proliferation, migration, and invasion abilities of glioma cell lines all showed a decrease. Then, we constructed the NEDD Index for gliomas. The nomogram indicated that this model could serve as an independent prognostic marker. Analysis of the tumour microenvironment and immune checkpoints revealed that the NEDD index was also correlated with immune cell infiltration and the expression levels of various immune checkpoints. CONCLUSION: The NEDD index can serve as a practical tool for predicting the prognosis of glioma patients, and it is correlated with immune cell infiltration and the expression levels of immune checkpoints.

Hypermethylation of the BRCA2 gene promoter and its co-hypermethylation with the BRCA1 gene promoter in patients with breast cancer.

BACKGROUND: The BRCA2 gene is an important tumour suppressor in breast cancer, and alterations in BRCA2 may lead to cancer progression. The aim of the study was to investigate the association of hypermethylation of the BRCA2 gene promoter and its co-hypermethylation with the BRCA1 gene promoter with the development and course of breast cancer in women. METHODS: This study included 74 women with breast cancer (tumour tissue samples and peripheral blood) and 62 women without oncological pathology (peripheral blood) - control group. RESULTS: Hypermethylation of the BRCA2 gene was significantly more frequently detected in the tumour tissue of women with breast cancer compared to their peripheral blood and peripheral blood of control subjects (p= 0.0006 and p= 0.00001, respectively). Hypermethylation of BRCA2 was more frequently detected in patients with breast cancer over the age of 50 and in patients with higher Ki67 expression levels (p= 0.045 and p= 0.045, respectively). There was a high frequency of unmethylated BRCA1 and BRCA2 gene combination in women of the control group compared to women with breast cancer, both in blood samples and tumour tissue samples (p= 0.014 and p= 0.00001, respectively). CONCLUSION: Our study confirms the hypothesis that BRCA2 hypermethylation plays an important role in the pathogenesis of breast cancer and the importance of assessing its co-hypermethylation with BRCA1 in predicting the course of the disease.

Endogenous base damage as a driver of genomic instability in homologous recombination-deficient cancers.

Homologous recombination (HR) is a high-fidelity DNA double-strand break (DSB) repair pathway. Both familial and somatic loss of function mutation(s) in various HR genes predispose to a variety of cancer types, underscoring the importance of error-free repair of DSBs in human physiology. While environmental sources of DSBs have been known, more recent studies have begun to uncover the role of endogenous base damage in leading to these breaks. Base damage repair intermediates often consist of single-strand breaks, which if left unrepaired, can lead to DSBs as the replication fork encounters these lesions. This review summarizes various sources of endogenous base damage and how these lesions are repaired. We highlight how conversion of base repair intermediates, particularly those with 5'or 3' blocked ends, to DSBs can be a predominant source of genomic instability in HR-deficient cancers. We also discuss how endogenous base damage and ensuing DSBs can be exploited to enhance the efficacy of Poly (ADP-ribose) polymerase inhibitors (PARPi), that are widely used in the clinics for the regimen of HR-deficient cancers.

Advancements in targeting tumor suppressor genes (p53 and BRCA 1/2) in breast cancer therapy.

Globally, among numerous cancer subtypes, breast cancer (BC) is one of the most prevalent forms of cancer affecting the female population. A female's family history significantly increases her risk of developing breast cancer. BC is caused by aberrant breast cells that proliferate and develop into tumors. It is estimated that 5-10% of breast carcinomas are inherited and involve genetic mutations that ensure the survival and prognosis of breast cancer cells. The most common genetic variations are responsible for hereditary breast cancer but are not limited to p53, BRCA1, and BRCA2. BRCA1 and BRCA2 are involved in genomic recombination, cell cycle monitoring, programmed cell death, and transcriptional regulation. When BRCA1 and 2 genetic variations are present in breast carcinoma, p53 irregularities become more prevalent. Both BRCA1/2 and p53 genes are involved in cell cycle monitoring. The present article discusses the current status of breast cancer research, spotlighting the tumor suppressor genes (BRCA1/2 and p53) along with structural activity relationship studies, FDA-approved drugs, and several therapy modalities for treating BC. Breast cancer drugs, accessible today in the market, have different side effects including anemia, pneumonitis, nausea, lethargy, and vomiting. Thus, the development of novel p53 and BRCA1/2 inhibitors with minimal possible side effects is crucial. We have covered compounds that have been examined subsequently (2020 onwards) in this overview which may be utilized as lead compounds. Further, we have covered mechanistic pathways to showcase the critical druggable targets and clinical and post-clinical drugs targeting them for their utility in BC.

Molecular genetic investigation of hereditary breast and ovarian cancer patients in the Southern Transdanubian region: widening the mutation spectrum and searching for new pathogenic variants using next-generation methods.

Hereditary breast and ovarian cancer is a well-known genetic condition, inherited mainly in an autosomal dominant way, which elevates the risk of developing malignancies at a young age in heterozygous carriers. Advances in new generation sequencing have enabled medical professionals to determine whether a patient is harbouring mutations in moderate- or high penetrance susceptibility genes. We conducted a retrospective analysis among 275 patients who underwent genetic counselling and multigene panel testing for hereditary breast and ovarian cancer syndrome in our department. From these patients 74.5% (205/275) were affected by some type of malignancy, while the remaining 25.5% (70/275) had a positive family history of different cancers, suggesting a genetic predisposition. These tests confirmed a genetic variant in 29.8% and 28.6% of these patient groups respectively. The results also mirrored our general knowledge concerning the genetic background of hereditary breast and ovarian cancer, as variants in either one of the BRCA1 and BRCA2 genes proved to be the most common cause among our patients with 41.5%. Our test also detected a novel mutation in the CDH1 gene and three patients with double heterozygosity in two different susceptibility genes. This study demonstrates the relevance of genetic counselling and non-BRCA gene sequencing among cancer patients and patients who fulfil the criteria for genetic testing, while also providing important details about the genetic profile of Hungarian patients.

R-loop functions in Brca1-associated mammary tumorigenesis.

Deleterious accumulation of R-loops, a DNA-RNA hybrid structure, contributes to genome instability. They are associated with BRCA1 mutation-related breast cancer, an estrogen receptor α negative (ERα-) tumor type originating from luminal progenitor cells. However, a presumed causality of R-loops in tumorigenesis has not been established in vivo. Here, we overexpress mouse Rnaseh1 (Rh1-OE) in vivo to remove accumulated R-loops in Brca1-deficient mouse mammary epithelium (BKO). R-loop removal exacerbates DNA replication stress in proliferating BKO mammary epithelial cells, with little effect on homology-directed repair of double-strand breaks following ionizing radiation. Compared to their BKO counterparts, BKO-Rh1-OE mammary glands contain fewer luminal progenitor cells but more mature luminal cells. Despite a similar incidence of spontaneous mammary tumors in BKO and BKO-Rh1-OE mice, a significant percentage of BKO-Rh1-OE tumors express ERα and progesterone receptor. Our results suggest that rather than directly elevating the overall tumor incidence, R-loops influence the mammary tumor subtype by shaping the cell of origin for Brca1 tumors.

The guidelines for clinical practice for carriers of germline mutations in hereditary breast, ovarian, prostate, and pancreatic cancer predisposition genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 (4.2024).

The Guidelines for Clinical Practice for carriers of pathogenic variants in clinically relevant cancer predisposition genes define the steps of primary and secondary prevention that should be provided to these individuals at high risk of developing hereditary cancer in the Czech Republic. The drafting of the guidelines was organized by the Oncogenetics Working Group of the Society for Medical Genetics and Genomics of J. E. Purkyne Czech Medical Society (SLG CLS JEP) in cooperation with the representatives of oncology and oncogynecology. The guidelines are based on the current recommendations of the National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO) and take into account the capacity of the Czech healthcare system.

Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.

Quantum-Dot-Encoded Beads-Enhanced CRISPR/Cas-Based Lateral-Flow Assay for the Amplification-Free, Sensitive, and Rapid Detection of Nucleic Acids in Breast Cancer.

Nucleic acid detection plays a pivotal role in the accurate diagnosis of diseases. The CRISPR/Cas detection system, noted for its significant utility in a variety of applications, often necessitates enhanced sensitivity or specific signal amplification strategies, particularly for detecting low-abundance biomarkers. In this study, we present a quantum-dot-encoded beads (QDB)-energized CRISPR/Cas12-based lateral-flow assay (QDB-CRISPR-LFA). This method enables amplification-free, sensitive, and rapid detection (<40 min) of BRCA-1. We validated our method using contrived reference samples and nucleic acids extracted from tumor cells. The QDB-CRISPR-LFA provides a visual, more rapid alternative to the traditional BRCA-1 real-time RT-PCR assay. Significantly, through the integration of CRISPR's specificity and the high signal output of QDB, the detection threshold for BRCA-1 has been reduced to the femtomolar level, representing an enhancement of 2-4 orders of magnitude over existing CRISPR/Cas detection methods. This advancement underscores the potential of our approach in advancing nucleic acid detection techniques, which is crucial for the early and precise diagnosis of diseases.

Current diagnostic and treatment options for pancreatic cancer in 2024.

Pancreatic ductal adenocarcinoma is a cancer disease with a very poor prognosis, which poses the third-leading cause of cancer-related deaths and whose incidence and mortality have been predicted to increase significantly in the upcoming years. Almost 80% of patients are diagnosed with advanced unresectable disease and therefore rely on palliative anticancer treatment with limited efficacy. However, even in case of 10-20 % of patients who have successfully undergone radical surgical resection of the localized disease and subsequent adjuvant chemotherapy, the vast majority will relapse within 2-3 years of surgery. The reasons can be found in late diagnosis due to the prolonged clinically asymptomatic course of the disease, complicated anatomical localization, significant tumor heterogeneity, which makes it difficult to test new drugs and, last but not least, in the presence of dense tumor stroma, that complicates the access of cytostatics and targeted drugs into the tumor tissue. Here we present a summary of current treatment options of localized and advanced pancreatic cancer, including molecular diagnostics and targeted treatment of small patients subgroups.

Homologous recombination deficiency (HRD) is associated with better prognosis and possibly causes a non-inflamed tumour microenvironment in nasopharyngeal carcinoma.

Homologous recombination deficiency (HRD) score is a reliable indicator of genomic instability. The significance of HRD in nasopharyngeal carcinoma (NPC), particularly its influence on prognosis and the immune microenvironment, has yet to be adequately explored. Understanding HRD status comprehensively can offer valuable insights for guiding precision treatment. We utilised three cohorts to investigate HRD status in NPC: the Zhujiang cohort from local collection and the Hong Kong (SRA288429) and Singapore (SRP035573) cohorts from public datasets. The GATK (genome analysis toolkit) best practice process was employed to investigate germline and somatic BRCA1/2 mutations and various bioinformatics tools and algorithms to examine the association between HRD status and clinical molecular characteristics. We found that individuals with a negative HRD status (no-HRD) exhibited a higher risk of recurrence [hazard ratio (HR), 1.43; 95% confidence interval (CI), 2.03-333.76; p = 0.012] in the Zhujiang cohort, whereas, in the Singapore cohort, they experienced a higher risk of mortality (HR, 26.04; 95% CI, 1.43-34.21; p = 0.016) compared with those in the HRD group. In vitro experiments demonstrated that NPC cells with BRCA1 knockdown exhibit heightened sensitivity to chemoradiotherapy. Furthermore, the HRD group showed significantly higher tumour mutational burden and tumour neoantigen burden levels than the no-HRD group. Immune infiltration analysis indicated that HRD tissues tend to have a non-inflamed tumour microenvironment. In conclusion, patients with HRD exhibit a comparatively favourable prognosis in NPC, possibly associated with a non-inflammatory immune microenvironment. These findings have positive implications for treatment stratification, enabling the selection of more precise and effective therapeutic approaches and aiding in the prediction of treatment response and prognosis to a certain extent.

Assessing the acceptability and appropriateness of a psychoeducational graphic novel about inherited cancer risk designed for men.

Men with germline pathogenic variants in BRCA1 or BRCA2 genes are at an increased lifetime risk for developing breast cancer, prostate cancer, and pancreatic cancer. Men report that managing clinical care is challenging because they are under-informed about their cancer risks. As the demand for genetic testing has increased, so too has the need to relay accurate and relatable genetic health information. This research developed and assessed the acceptability and appropriateness of a psychoeducational graphic novel designed for men to improve their cancer risk knowledge, manage their cancer-related uncertainty, and increase their intent to disclose their BRCA1/2 risks to family members and healthcare providers. Through purposive and snowball sampling, men (n = 20) and certified genetic counselors (CGCs; n = 15) participated in semi-structured interviews assessing the acceptability and appropriateness of the graphic novel. Interviews were audio-recorded, transcribed, and thematically analyzed. Both reported that the graphic novel confirmed risk information provided helpful resources, included relatable storylines, and had a unique visual appeal. Some men remained unsure about how to perform recommended screenings and how to talk to family members, particularly children, about BRCA1/2 test results after assessing the graphic novel. CGCs also discussed the helpfulness of the graphic novel for their practice. Given that this psychoeducational graphic novel was appealing to men and CGCs, it shows promise as an acceptable approach that may assist men in managing their cancer risks and communicating their genetic risk information to family members and healthcare providers.

The Interaction of Calcium-Sensing Receptor with KIF11 Enhances Cisplatin Resistance in Lung Adenocarcinoma via BRCA1/cyclin B1 pathway.

Cisplatin (DDP) is commonly used in the treatment of non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD), and the primary cause for its clinical inefficacy is chemoresistance. Here, we aimed to investigate a novel mechanism of chemoresistance in LUAD cells, focusing on the calcium-sensing receptor (CaSR). In this study, high CaSR expression was detected in DDP-resistant LUAD cells, and elevated CaSR expression is strongly correlated with poor prognosis in LUAD patients receiving chemotherapy. LUAD cells with high CaSR expression exhibited decreased sensitivity to cisplatin, and the growth of DDP-resistant LUAD cells was inhibited by cisplatin treatment in combination with CaSR suppression, accompanied by changes in BRCA1 and cyclin B1 protein expression both in vitro and in vivo. Additionally, an interaction between CaSR and KIF11 was identified. Importantly, suppressing KIF11 resulted in decreased protein levels of BRCA1 and cyclin B1, enhancing the sensitivity of DDP-resistant LUAD cells to cisplatin with no obvious decrease in CaSR. Here, our findings established the critical role of CaSR in promoting cisplatin resistance in LUAD cells by modulating cyclin B1 and BRCA1 and identified KIF11 as a mediator, highlighting the potential therapeutic value of targeting CaSR to overcome chemoresistance in LUAD.

Immediate Psychological Implications of Risk-Reducing Mastectomies in Women With Increased Risk of Breast Cancer: A Comparative Study.

BACKGROUND: Risk-reducing mastectomy is recommended for high-risk patients but may have significant psychological consequences. This study aimed to determine the differences in anxiety, depressive symptomatology, body image and quality of life in women with an increased risk of breast cancer immediately before and after undergoing risk-reducing mastectomy. METHODS: Eighty-eight women with an increased risk of breast cancer due to BRCA1/2 mutations or a previous cancer diagnosis participated in this study. Instruments used were the Hospital Anxiety and Depression Scale, Body Image Scale and the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 and Breast 23, administered 15-30 days before and after surgery. RESULTS: Following surgery, there was an immediate and significant worsening in anxiety, depressive symptomatology and body image. There was a significant deterioration in global, physical, role, and social functioning, as well as in body image and sexual enjoyment scales. Additionally, there were increases in fatigue, nausea and vomiting, constipation, dyspnoea, insomnia, appetite loss, perceived financial difficulties, pain, systemic therapy side effects, and breast and arm symptoms. However, there was an improvement in future perspective. These changes occurred independently of whether participants had a cancer diagnosis or BRCA1/2 mutation. CONCLUSION: Risk-reducing mastectomies have immediate psychological consequences. While these procedures improve future health perspective, they increase anxiety and depressive symptomatology and decrease body image and quality of life, regardless of cancer diagnosis or BRCA1/2 mutation. These findings highlight the psychological consequences of such surgical procedures, emphasizing the need for comprehensive psychological interventions both before and after surgery.

Aqueous Extracts of Ocimum gratissimum Sensitize Hepatocellular Carcinoma Cells to Cisplatin through BRCA1 Inhibition.

Ocimum gratissimum (O. gratissimum), a medicinal herb with antifungal and antiviral activities, has been found to prevent liver injury and liver fibrosis and induce apoptosis in hepatocellular carcinoma (HCC) cells. In this study, we evaluated the effect of aqueous extracts of O. gratissimum (OGE) on improving the efficacy of chemotherapeutic drugs in HCC cells. Proteomic identification and functional assays were used to uncover the critical molecules responsible for OGE-induced sensitization mechanisms. The antitumor activity of OGE in combination with a chemotherapeutic drug was evaluated in a mouse orthotopic tumor model, and serum biochemical tests were further utilized to validate liver function. OGE sensitized HCC cells to the chemotherapeutic drug cisplatin. Proteomic analysis and Western blotting validation revealed the sensitization effect of OGE, likely achieved through the inhibition of breast cancer type 1 susceptibility protein (BRCA1). Mechanically, OGE treatment resulted in BRCA1 protein instability and increased proteasomal degradation, thereby synergistically increasing cisplatin-induced DNA damage. Moreover, OGE effectively inhibited cell migration and invasion, modulated epithelial-to-mesenchymal transition (EMT), and impaired stemness properties in HCC cells. The combinatorial use of OGE enhanced the efficacy of cisplatin and potentially restored liver function in a mouse orthotopic tumor model. Our findings may provide an alternate approach to improving chemotherapy efficacy in HCC.