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.

Synthetic lethality approaches in BRCA1/2-mutated cancers have focused on PARP inhibitors, which are subject to high rates of innate or acquired resistance in patients. In this study, we used CRISPR/Cas9-based screening to identify DNA ligase I (LIG1) as a novel target for synthetic lethality in BRCA1-mutated cancers. Publicly available data supported LIG1 hyperdependence of BRCA1 mutant cells across a variety of breast and ovarian cancer cell lines. We used CRISPRn, CRISPRi, RNAi, and protein degradation to confirm the lethal effect of LIG1 inactivation at the DNA, RNA, and protein level in BRCA1 mutant cells in vitro. LIG1 inactivation resulted in viability loss across multiple BRCA1-mutated cell lines, whereas no effect was observed in BRCA1/2 wild-type cell lines, demonstrating target selectivity for the BRCA1 mutant context. On-target nature of the phenotype was demonstrated through rescue of viability with exogenous wild-type LIG1 cDNA. Next, we demonstrated a concentration-dependent relationship of LIG1 protein expression and BRCA1 mutant cell viability using a titratable, degradable LIG1 fusion protein. BRCA1 mutant viability required LIG1 catalytic activity, as catalytically dead mutant LIG1K568A failed to rescue viability loss caused by endogenous LIG1 depletion. LIG1 perturbation produced proportional increases in PAR staining in BRCA1 mutant cells, indicating a mechanism consistent with the function of LIG1 in sealing ssDNA nicks. Finally, we confirmed LIG1 hyperdependence in vivo using a xenograft model in which LIG1 loss resulted in tumor stasis in all mice. Our cumulative findings demonstrate that LIG1 is a promising synthetic lethal target for development in patients with BRCA1-mutant cancers.

Breast cancer initiation and progression are driven by various oncogenic factors and their effects on the surrounding microenvironments. Through integrative analysis of ChIP-sequencing and RNA-sequencing with fast proliferating mammary epithelial cells from pregnant Brca1MKO and wild type (WT) mice, we found that elevated Smyd3-Shcbp1 signaling is featured with activation of the Ras-MAPK pathway and increased transcription activity in both premalignant mammary epithelium and tumor cells. Smyd3-Shcbp1 signaling shapes the tumor immunosuppressive microenvironment (TIME) and is associated with immune therapy resistance to PD1 antibody treatment. Trametinib, a potent inhibitor of MEK/MAPK, could reverse the expression of Smyd3 and Shcbp1 in both Brca1 mutant and WT tumor bearing mice. We further demonstrated that the combinatory treatment of trametinib together with PD1 antibody enhances the function of effector T cells, sensitizing tumors with elevated Smyd3 and Shcbp1 signaling to αPD1 treatment. This study advances the understanding of breast tumor progression and provides a new selective strategy for breast cancer patients.

The Bcl-2 family's anti-apoptotic proteins, particularly Mcl-1, offer a viable avenue for cancer treatment since cancer cells can undergo apoptosis when their selective suppression occurs. Mcl-1 is essential for controlling the advancement of the cell cycle, as well as apoptosis. There is a constant clinical need for more potent treatments for breast and ovarian malignancies, even with advancements in the discovery of anticancer drugs. By synthesizing cyanopyrimidine derivatives that demonstrate both dual inhibitory activity against Mcl-1 and Bcl-2, and successful cell cycle arrest, our research seeks to contribute to the development of innovative therapeutic medicines. We created a number of new 6-substituted cyanopyrimidines and tested their anticancer effects on SKOV-3 and MCF-7 cell lines as well as apoptosis and cell cycle arrest assays.

Breast cancer remains one of the most prevalent diseases worldwide, primarily affecting women. Its heterogeneous nature poses a significant challenge in the development of effective and targeted treatments. Molecular characterization has enabled breast cancer to be classified into four main subtypes: luminal A, luminal B, HER2-positive, and triple-negative breast cancer, based on hormone receptor expression and HER2 status. A deeper understanding of these molecular markers and their associated signaling pathways, such as MAPK and PI3K/AKT, is essential for improving prognosis and optimizing treatment strategies. Currently, several therapeutic agents are utilized in neoadjuvant and adjuvant therapies, often in combination with surgical interventions. However, emerging evidence highlights the growing challenge of drug resistance, which significantly limits the efficacy of existing treatments. Addressing this issue may require innovative approaches, including combination therapies and precision medicine strategies, tailored to the molecular profile of each patient. Therefore, a comprehensive understanding of the pathophysiologic mechanisms driving breast cancer progression and resistance is crucial for the development of advanced targeted therapies with greater precision and efficacy. This review aims to explore recent advancements in molecular research related to breast cancer subtypes and provide a critical analysis of current therapeutic approaches within the framework of precision medicine.

To identify potential therapeutic targets and evaluate the safety profiles for Idiopathic Pulmonary Fibrosis (IPF) using a comprehensive multi-omics approach.

We integrated genomic and transcriptomic data to identify therapeutic targets for IPF. First, we conducted a transcriptome-wide association study (TWAS) using the Omnibus Transcriptome Test using Expression Reference Summary data (OTTERS) framework, combining plasma expression quantitative trait loci (eQTL) data with IPF Genome-Wide Association Studies (GWAS) summary statistics from the Global Biobank (discovery) and Finngen (duplication). We then applied Mendelian randomization (MR) to explore causal relationships. RNA-seq co-expression analysis (bulk, single-cell and spatial transcriptomics) was used to identify critical genes, followed by molecular docking to evaluate their druggability. Finally, phenome-wide MR (PheW-MR) using GWAS data from 679 diseases in the UK Biobank assessed the potential adverse effects of the identified genes.

We identified 696 genes associated with IPF in the discovery dataset and 986 genes in the duplication dataset, with 126 overlapping genes through TWAS. MR analysis revealed 29 causal genes in the discovery dataset, with 13 linked to increased and 16 to decreased IPF risk. Summary data-based MR (SMR) confirmed six essential genes: ANO9, BRCA1, CCDC200, EZH1, FAM13A, and SFR1. Bulk RNA-seq showed FAM13A upregulation and SFR1 and EZH1 downregulation in IPF. Single-cell RNA-seq revealed gene expression changes across cell types. Molecular docking identified binding solid affinities for essential genes with respiratory drugs, and PheW-MR highlighted potential side effects.

We identified six key genes-ANO9, BRCA1, CCDC200, EZH1, FAM13A, and SFR1-as potential drug targets for IPF. Molecular docking revealed strong drug affinities, while PheW-MR analysis highlighted therapeutic potential and associated risks. These findings offer new insights for IPF treatment and further investigation of potential side effects.

This article provides a comprehensive analysis of the signaling pathways implicated in breast cancer (BC), the most prevalent malignancy among women and a leading cause of cancer-related mortality globally. Special emphasis is placed on the structural dynamics of protein complexes that are integral to the regulation of these signaling cascades. Dysregulation of cellular signaling is a fundamental aspect of BC pathophysiology, with both upstream and downstream signaling cascade activation contributing to cellular process aberrations that not only drive tumor growth, but also contribute to resistance against current treatments. The review explores alterations within these pathways across different BC subtypes and highlights potential therapeutic strategies targeting these pathways. Additionally, the influence of specific mutations on therapeutic decision-making is examined, underscoring their relevance to particular BC subtypes. The article also discusses both approved therapeutic modalities and ongoing clinical trials targeting disrupted signaling pathways. However, further investigation is necessary to fully elucidate the underlying mechanisms and optimize personalized treatment approaches.

Multiple primary cancers (MPC) are an indicator of potential hereditary cancer predisposition syndrome. There remains insufficient data on genetic testing outcomes and the optimal testing panel for MPC. We evaluated the prevalence of MPC, the spectrum of pathogenic germline variants (PGVs) and the role of extended panel testing in MPC.

Cancer patients seen in a cancer genetics clinic in a tertiary cancer centre in Singapore from 2000 to 2023 were included. Clinical characteristics, PGV and patterns of cancer were analysed. Most patients were tested with 49 genes, but in a selected 156 patients with MPC, extended testing with 216 genes was carried out.

Of 3514 cancer patients (male = 17.9%, female = 82.1%), 668 (19%) had MPC (2 primaries, n = 570; 3 primaries, n = 81; ≥4 primaries, n = 17). The most common tumour pairs were breast-breast (33.2%), breast-ovary (8.9%), breast-endometrial (4.6%) and endometrial-ovary (4.6%). Patients with MPC had a younger median age of first cancer. Of the MPC patients, 29.4% tested positive for at least one PGV, with PGVs detected in BRCA1/2 (39.9%), other homologous recombination repair (HRR) genes (18.9%), mismatch repair (MMR) genes (11.2%) and TP53 (7%) genes. HRR genes included ATM, BARD1, BRIP1, CHEK2, PALB2, FANCL, RAD51C and RAD51D, while MMR genes included MLH1, MSH2, MSH6 and PMS2. MPC patients were more likely to have PGVs in TP53 and BARD1 compared with patients with single primary cancer. Extended testing detected more PGVs in MPC despite initial noninformative testing. It increased the number of PGVs detected in less established cancer predisposition genes, which include CFTR, SPINK1, TNFRSF13B, TET2, ADA, CDKN1C, CTNNA1, DDX41, HAX1, RECQL4 and MBD4.

Patients with MPC were more likely to harbour a PGV. Extended testing improved PGV detection rates, particularly for less well-known cancer predisposition genes.

Breast cancer, the most prevalent cancer affecting women worldwide, poses a significant cardio-oncological burden. Despite advancements in novel therapeutic strategies, anthracyclines, HER2 antagonists, and radiation remain the cornerstones of oncological treatment. However, each carries a risk of cardiotoxicity, though the molecular mechanisms underlying these adverse effects differ. Common mechanisms include DNA damage response, increased reactive oxygen species, and mitochondrial dysfunction, which are key areas of ongoing research for potential cardioprotective strategies. Since these mechanisms are also essential for effective tumor cytotoxicity, we explore tumor-specific effects, particularly in hereditary breast cancer linked to BRCA1 and BRCA2 mutations. These genetic variants impair DNA repair mechanisms, increase the risk of tumorigenesis and possibly for cardiotoxicity from treatments such as anthracyclines and HER2 antagonists. Novel therapies, including immune checkpoint inhibitors, are used in the clinic for triple-negative breast cancer and improve the oncological outcomes of breast cancer patients. This review discusses the molecular mechanisms underlying BRCA dysfunction and the associated pathological pathways. It gives an overview of preclinical models of breast cancer, such as genetically engineered mouse models, syngeneic murine models, humanized mouse models, and various in vitro and ex vivo systems and models to study cardiovascular side effects of breast cancer therapies. Understanding the underlying mechanism of cardiotoxicity and developing cardioprotective strategies in preclinical models are essential for improving treatment outcomes and reducing long-term cardiovascular risks in breast cancer patients.

Worldwide, breast cancer is the leading cause of death in women with cancers. Given this situation, new approaches to treatment are urgently needed. Tumor Suppressor Genes (TSGs) defects play a crucial role in tumor development, and recent studies propose their reactivation as a promising way for clinical intervention in breast cancer. Here, we performed detailed evolutionary analyses of 241 breast cancer TSGs across 25 mammalian genomes, revealing 28 genes under strong positive selection. These genes exhibit elevated molecular pressure in codons corresponding to amino acids located in crucial protein domains and motifs. Notably, one positively selected site in the BRCA1 C-terminal domain is known for its role in DNA damage response, suggesting potential interference with DNA repair mechanisms. Moreover, the substitution of some other sites found in important key motifs, namely two codons in BRCA2 (752 and 939) localized within the phosphoinositide-3-OH-kinase-related and playing a crucial role in the DNA repair and the DNA damage checkpoints. Our findings could be inspirational to foster future recommendations for drug-targeting sites and further illuminate the function of these proteins. Finally, the code developed in our study is delivered in the Automated tool for positive selection (ATPs) ( https://github.com/APS-P/Automated-Tool-for-Positive-Selection-ATPS-/wiki ) to assist the easy reproducibility and support future evolutionary genomics analyses.

Breast cancer is one of the leading causes of mortality among women, primarily due to its complex molecular landscape and heterogeneous nature. The tendency of breast cancer patients to develop metastases poses significant challenges in clinical management. Notably, mutations in the breast cancer gene 1 (BRCA1) significantly elevate breast cancer risk. The current research endeavors employ diverse molecular approaches, including RNA, DNA, and protein studies, to explore avenues for the early diagnosis and treatment of breast cancer. Recent attention has shifted towards long non-coding RNAs (lncRNAs) as promising diagnostic, prognostic, and therapeutic targets in the multifaceted progression of breast cancer. Among these, long intergenic non-coding RNAs (lincRNAs), a specific class of lncRNAs, play critical roles in regulating various aspects of tumorigenesis, including cell proliferation, apoptosis, epigenetic modulation, tumor invasion, and metastasis. Their distinctive expression patterns in cellular and tissue contexts underscore their importance in breast cancer development and progression. Harnessing lincRNAs' sensitivity and precision as diagnostic, therapeutic, and prognostic markers holds significant promise for the clinical management of breast cancer. However, the potential of lincRNAs remains relatively underexplored, particularly in the context of BRCA1-mutated breast cancer and other clinicopathological parameters such as receptor status and patient survival. Consequently, there is an urgent need for comprehensive investigations into novel diagnostic and prognostic breast cancer biomarkers. This review examines the roles of lincRNAs associated with BRCA1 in the landscape of breast cancer, highlighting the potential avenues for future research and clinical applications.

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.

Zinc is an essential micronutrient that participates in a multitude of cellular and biochemical processes. It is indispensable for normal growth and the maintenance of physiological functions. As one of the most significant trace elements in the body, zinc fulfills three primary biological roles: catalytic, structural, and regulatory. It serves as a cofactor in over 300 enzymes, and more than 3000 proteins require zinc, underscoring its crucial role in numerous physiological processes such as cell division and growth, immune function, tissue maintenance, as well as synthesis protein and collagen synthesis. Zinc deficiency has been linked to increased oxidative stress and inflammation, which may contribute to the pathogenesis of a multitude of diseases, like neurological disorders and cancer. In addition, zinc is a key constituent of zinc-binding proteins, which play a pivotal role in maintaining cellular zinc homeostasis. This review aims to update and expand upon the understanding of zinc biology, highlighting the fundamental roles of zinc in biological processes and the health implications of zinc deficiency. This work also explores the diverse functions of zinc in immune regulation, cellular growth, and neurological health, emphasizing the need for further research to fully elucidate the therapeutic potential of zinc supplementation in disease prevention and management.

Breast and ovarian cancers are significant global health challenges, with inherited variations in breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2) substantially increasing the risk, aggressiveness, and early onset of these diseases. This work aimed to examine pathogenic variants (PVs) in BRCA1 and BRCA2 databases that include Mexican populations. A systematic review of literature and data mining spanning from 2002 to 2023 was conducted. Articles published in journals indexed in SCImago quartiles Q1 to Q4 were screened. Databases were paired, standardized, and enriched with data from reputable global platforms: Genome Data Viewer, dbSNP, ClinVar, gnomAD browser, Breast Cancer Information Core (BIC), ClinGen, Varsome, Human Genome Variation Society (HGVS), Bioproject, Ensembl, Gene NIH NCIB, UniProt, and BRCA Exchange. Outcomes included data from 9,026 Mexican genotypes, identifying 657 PVs. Genetic mapping revealed certain exons, notably exon 10 of BRCA1 and exon 11 of BRCA2, as highly mutagenic hot spots. The most frequent alteration was a large deletion in BRCA1 (ex9-12del), associated with a founder effect originating from a common Mexican ancestor. Finally, we constructed a genetic map containing all the single nucleotide variants (SNVs) and large rearrangements presented in the analyzed databases.

Conditions associated with BRCA1/2 pathogenic (PVs) or likely pathogenic variants (LPVs) are often severe. The early detection of carrier status is ideal, as it provides options for effective case management.

The study involved 58 patients with a personal and familial history of breast cancer (BC) who underwent genetic testing at the Regional Centre for Medical Genetics Dolj over a three-year period. An immunohistochemical panel (HER2, ER, PR, and Ki-67) was used to define the molecular subtypes of breast tumors. The AmpliSeq for Illumina BRCA Panel was used to evaluate germline variants in the BRCA1 and BRCA2 genes in patients with BC. The χ2 test and Fisher's exact test were used to compare the different parameters studied.

Our findings revealed that 15.5% of the patients carried either BRCA1 or BRCA2 PVs or LPVs. BRCA1 carriers had aggressive tumors whereas BRCA2 carriers had rather low-grade tumors.

The study revealed that PVs in both BRCA genes have a significant frequency among BC patients in our region, and BRCA1 carriers tend to develop more aggressive tumors than carriers of BRCA2 PVs and patients with no germline PVs in either of the two genes. These observations could provide new epidemiologic data for this disease in our region and contribute further to the development of national screening strategies.

Taxanes are frequently used anticancer drugs known to kill tumor cells by inducing mitotic aberrations and segregation defects. A defining feature of specific cancers, notably triple-negative breast cancer (TNBC) and particularly those deficient in BRCA1, is chromosomal instability (CIN). Here, we focused on understanding the mechanisms of docetaxel-induced cytotoxicity, especially in the context of BRCA1-deficient TNBC. Using functional genetic screens in CIN+ cells, we identified genes that mediate docetaxel response and found an interaction between Huntingtin (HTT) and BRCA1-associated protein-1 (BAP1). We employed Brca1-/-;p53-/- mammary tumor cells, derived from genetically engineered mouse tumors that closely mimic the human disease, to investigate the role of these genes in CIN+ BRCA1-deficient cells. Specifically, we observed that loss of HTT sensitizes CIN+ BRCA1-deficient mammary tumor cells to docetaxel by shortening mitotic spindle poles and increasing spindle multipolarity. In contrast, BAP1 depletion protected cells against these spindle aberrations by restoring spindle length and enhancing mitotic clustering of the extra centrosomes. In conclusion, our findings shed light on the roles of HTT and BAP1 in controlling mitotic spindle multipolarity and centrosome clustering, specifically in the absence of BRCA1. This affects the response to microtubule-targeting agents and suggests that further studies of the interaction of these genes with the mitotic spindle may provide useful insights into how to target CIN+ cells, particularly in the challenging therapeutic landscape of BRCA1-deficient TNBC.

The accurate interpretation of the BRCA1/2 variant is critical for diagnosing and treating hereditary breast and ovarian cancers. ClinVar is a widely used public database for genetic variants. Conflicting classifications of pathogenicity can occur when different submitters categorize the same genetic variant inconsistently as pathogenic (PV), likely pathogenic (LPV), likely benign (LBV), benign (BV), or a variant of uncertain significance (VUS). The conflicting ClinVar BRCA1/2 variant classifications hinder clinical decision making. We reinterpreted 450 BRCA1 missense variants with conflicting interpretations in ClinVar (accessed on 20 December 2022).

VarSome and the BRCA1/BRCA2: CanVIG-UK gene-specific guidance (CanVIG-UK) classifications were compared, and the five original classifications were consolidated into three categories (PV/LPV, VUS, and BV/LBV). Consensus analysis was performed between re-extracted ClinVar data and VarSome and CanVIG-UK results.

The three-category classification of the variants resulted in an overall concordance rate of 58.9% for BRCA1 missense variant interpretation between CanVIG-UK and VarSome, with VarSome having rates of 11.3, 24.7, and 64.0% for PV/LPV, VUS, and BV/LBV classifications and CanVIG-UK having rates of 11.1, 51.6, and 37.3% for P/LPV, VUS, and BV/LBV classifications, respectively. No variants classified as PV/LPV in VarSome were classified as BV/LBV in CanVIG-UK and vice versa. By 1 May 2024, 3.8% (17/450) of these conflicting variants reached a consensus classification in ClinVar and were definitively classified (9 PV/LPV, 1 VUS, and 7 BV/LBV).

VarSome and CanVIG-UK have different features that help improve the accuracy of pathogenicity classification, highlighting the potential complementary use of both tools to support clinical decision making.

BReast CAncer gene 1 (BRCA1) and BReast CAncer gene 2 (BRCA2) encode for tumor suppressor proteins which are critical regulators of the Homologous Recombination (HR) pathway, the most precise and important DNA damage response mechanism. Dysfunctional HR proteins cannot repair double-stranded DNA breaks in mammalian cells, a situation called HR deficiency. Since their identification, pathogenic variants and other alterations of BRCA1 and BRCA2 genes have been associated with an increased risk of developing mainly breast and ovarian cancer. Interestingly, HR deficiency is also detected in tumors not carrying BRCA1/2 mutations, a condition termed "BRCAness".

One of the main mechanisms causing the BRCAness phenotype is the methylation of the BRCA1/2 promoters, and this epigenetic modification is associated with carcinogenesis and poor prognosis mainly among patients with breast and ovarian cancer. BRCA1 promoter methylation has been suggested as an emerging biomarker of great predictive significance, especially concerning Poly (ADP-ribose) Polymerase inhibitors (PARP inhibitor-PARPi) responsiveness, along with or beyond BRCA1/2 mutations. However, as its clinical exploitation is still insufficient, the impact of BRCA1/2 promoter methylation status needs to be further evaluated. The current review aims to gather the latest findings about the mechanisms that underline BRCA1/2 function as well as the molecular characteristics of tumors associated with BRCA1/2 defects, by focusing on DNA methylation. Furthermore, we critically analyze their translational meaning and the validity of BRCA methylation biomarkers in predicting treatment response.

We believe that BRCA1/2 methylation alone or combined with other biomarkers in a clinical setting is expected to change the scenery in prognosis and predicting treatment response in multiple cancer types and is worthy of further attention. The quantitative BRCA1 promoter methylation assessment might predict treatment response in PARPi and analysis of BRCA1/2 methylation in liquid biopsy might define patient subgroups at different time points that may benefit from PARPi. Finally, we suggest a pipeline that could be implemented in liquid biopsy to aid precision pharmacotherapy in BRCA-associated tumors.

Here we estimate the cost-effectiveness of olaparib in the Spanish National Health Service (SNHS) as adjuvant treatment of early germline mutations in the BRCA1/2 genes (gBRCAm) HER2-negative (HER2neg) breast cancer (BC) with high risk of recurrence.

A semi-Markov model was adapted to the Spanish healthcare setting, using the perspective of the SNHS, and a lifetime horizon. Two scenarios were compared: receiving olaparib versus standard of care (SoC) treatment. The model comprised five health states and included the clinical results of the OlympiA trial, along with the direct healthcare costs associated with the use of early BC and subsequent treatment resources (€2023). A discount rate of 3% was applied for future cost and quality-of-life outcomes. A probabilistic sensitivity analysis (PSA) was carried out.

The introduction of olaparib as adjuvant treatment for patients with early gBRCAm HER2neg BC with high risk of recurrence could involve an incremental cost of €44,273 and €50,164, with an improvement of 1.14 and 1.28 quality-adjusted life years (QALYs) for hormone receptor-positive (HR+) and triple-negative (TN) patients, respectively. Therefore, adjuvant olaparib could be cost-effective for early gBRCAm HER2neg BC, with an incremental cost-effectiveness ratio of €38,839/QALY and €39,084/QALY for HR+ and TN patients, respectively. The results from the PSA showed that 75.7% and 82.2% of the simulations fell below the €60,000/QALY threshold.

Olaparib as adjuvant treatment could be cost-effective in gBRCAm patients with early HER2neg BC in Spain.

The p53 is a crucial tumor suppressor and transcription factor that participates in apoptosis and senescence. It can be activated upon DNA damage to regulate the expression of a series of genes. Previous studies have demonstrated that some specific lncRNAs are part of the TP53 regulatory network. To enhance our understanding of the relationship between lncRNAs and P53 in cancers, we review the localization, structure, and function of some lncRNAs that are related to the mechanisms of the p53 pathway or serve as p53 transcriptional targets.

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.

Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer that encompasses several distinct subtypes. Recent advances in immunotherapy offer a promising future for the treatment of these highly heterogeneous and readily metastatic tumors. Despite advancements, the efficacy of immunotherapy remains limited as shown by unimproved efficacy of PD-L1 biomarker and limited patient benefit. To enhance the effectiveness of TNBC immunotherapy, we conducted investigation on the microenvironment, and corresponding therapeutic interventions of TNBC and recommended further investigation into the identification of additional biomarkers that can facilitate the subtyping of TNBC for more targeted therapeutic approaches. TNBC is a highly aggressive subtype with dismal long-term survival due to the lack of opportunities for traditional endocrine and targeted therapies. Recent advances in immunotherapy have shown promise, but response rates can be limited due to the heterogeneous tumor microenvironments and developed therapy resistance, especially in metastatic cases. In this review, we will investigate the tumor microenvironment of TNBC and corresponding therapeutic interventions. We will summarize current subtyping strategies and available biomarkers for TNBC immunotherapy, with a particular emphasis on the need for further research to identify additional prognostic markers and refine tailored therapies for specific TNBC subtypes. These efforts aim to improve treatment sensitivity and ultimately enhance survival outcomes for advanced-stage TNBC patients.

BRCA1 is one of the most frequently-mutated tumor suppressor genes in ovarian and breast cancers. Loss of BRCA1 triggers homologous recombination (HR) repair deficiency, consequently leading to genomic instability and PARP inhibitors (PARPi)-associated synthetic lethality. Although, the roles of BRCA1 in DNA repair and replication have been extensively investigated, its tumor suppressive functions beyond genome safeguard remain poorly understood. Here, we report that BRCA1 promotes ferroptosis susceptibility through catalyzing K6-linked polyubiquitination of GPX4 and subsequently accelerating GPX4 degradation. Depletion of BRCA1 induces ferroptosis resistance in ovarian cancer cells due to elevated GPX4 protein, and silence of GPX4 significantly suppresses the growth of BRCA1-deficient ovarian cancer xenografts. Importantly, we found that PARPi triggers ferroptosis in ovarian cancer cells, inhibition of GPX4 markedly increase PARPi-induced ferroptosis in BRCA1-deficient ovarian cancer cells. Combined treatment of GPX4 inhibitor and PARPi produces synergistic anti-tumor efficacy in BRCA1-deficient ovarian cancer cells, patient derived organoid (PDO) and xenografts. Thus, our study uncovers a novel mechanism via which BRCA1 exerts tumor suppressive function through regulating ferroptosis, and demonstrates the potential of GPX4 as a therapeutic target for BRCA1-mutant cancers.

Proteins are the most common types of biomarkers used in breast cancer (BC) theranostics and management. By definition, a biomarker must be a relevant, objective, stable, and quantifiable biomolecule or other parameter, but proteins are known to exhibit the most variate and profound structural and functional variation. Thus, the proteome is highly dynamic and permanently reshaped and readapted, according to changing microenvironments, to maintain the local cell and tissue homeostasis. It is known that protein posttranslational modifications (PTMs) can affect all aspects of protein function. In this review, we focused our analysis on the different types of PTMs of histological biomarkers in BC. Thus, we analyzed the most common PTMs, including phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, palmitoylation, myristoylation, and glycosylation/sialylation/fucosylation of transcription factors, proliferation marker Ki-67, plasma membrane proteins, and histone modifications. Most of these PTMs occur in the presence of cellular stress. We emphasized that these PTMs interfere with these biomarkers maintenance, turnover and lifespan, nuclear or subcellular localization, structure and function, stabilization or inactivation, initiation or silencing of genomic and non-genomic pathways, including transcriptional activities or signaling pathways, mitosis, proteostasis, cell-cell and cell-extracellular matrix (ECM) interactions, membrane trafficking, and PPIs. Moreover, PTMs of these biomarkers orchestrate all hallmark pathways that are dysregulated in BC, playing both pro- and/or antitumoral and context-specific roles in DNA damage, repair and genomic stability, inactivation/activation of tumor-suppressor genes and oncogenes, phenotypic plasticity, epigenetic regulation of gene expression and non-mutational reprogramming, proliferative signaling, endocytosis, cell death, dysregulated TME, invasion and metastasis, including epithelial-mesenchymal/mesenchymal-epithelial transition (EMT/MET), and resistance to therapy or reversal of multidrug therapy resistance. PTMs occur in the nucleus but also at the plasma membrane and cytoplasmic level and induce biomarker translocation with opposite effects. Analysis of protein PTMs allows for the discovery and validation of new biomarkers in BC, mainly for early diagnosis, like extracellular vesicle glycosylation, which may be considered as a potential source of circulating cancer biomarkers.

Statins, widely used cardiovascular drugs that lower cholesterol by inhibiting HMG-CoA reductase, have been increasingly recognized for their potential anticancer properties. This study elucidates the underlying mechanism, revealing that statins exploit Synthetic Lethality, a principle where the co-occurrence of two non-lethal events leads to cell death. Our computational analysis of approximately 37,000 SL pairs identified statins as potential drugs targeting genes involved in SL pairs with metastatic genes. In vitro validation on various cancer cell lines confirmed the anticancer efficacy of statins. This data-driven drug repurposing strategy provides a molecular basis for the anticancer effects of statins, offering translational opportunities in oncology.

Repetitive sequences play an indispensable role in gene expression, transcriptional regulation, and chromosome arrangements through trans and cis regulation. In this review, focusing on recent advances, we summarize the epigenetic regulatory mechanisms of repetitive sequences in embryonic stem cells. We aim to bridge the knowledge gap by discussing DNA damage repair pathway choices on repetitive sequences and summarizing the significance of chromatin organization on repetitive sequences in response to DNA damage. By consolidating these insights, we underscore the critical relationship between the stability of repetitive sequences and early embryonic development, seeking to provide a deeper understanding of repetitive sequence stability and setting the stage for further research and potential therapeutic strategies in developmental biology and regenerative medicine.

BACKGROUND Hereditary breast cancer arising in BRCA1-deficient patients is commonly diagnosed as invasive carcinoma of no special type (NST) with medullary features, while invasive lobular carcinoma (ILC) appears to be significantly under-represented in BRCA1 mutation carriers. We report a case of pleomorphic ILC arising in a 28-year-old woman harboring a germline BRCA1 c.3756_3759delGTCT p.(Ser1253Argfs*10) pathogenic variant. CASE REPORT A nulliparous 28-year-old woman with a family history of BRCA1 mutation presented to the symptomatic breast clinic with a several-week history of a left 80-mm breast lump. Core biopsy established a diagnosis of a poorly differentiated triple-negative breast cancer (TNBC) of pleomorphic lobular phenotype. Her clinical diagnosis was cT3, N0, M0, cStageIIB. The MDT recommended CT staging, MRI breast imaging and neoadjuvant chemotherapy (NACT). PET CT imaging showed no evidence of distant metastatic disease. The patient had a good radiological response to NACT with a FEC-T carboplatin regimen. Post-NACT imaging showed a residual cystic mass and the patient underwent a mastectomy and sentinel lymph node biopsy with plans for a delayed latissimus dorsi reconstruction following her adjuvant radiotherapy treatment. A complete pathological response was subsequently demonstrated without any evidence of metastatic disease. CONCLUSIONS This case is the first report of pleomorphic ILC with a triple-negative receptor status and a complete pathological response in a BRCA1 mutation carrier. Our study expands the heterogeneous spectrum of TNBC and contributes to a better understanding of the molecular genetic landscape that characterizes invasive pleomorphic lobular neoplasia.

Breast cancer is a global health issue affecting countries worldwide, imposing a significant economic burden due to expensive treatments and medical procedures, given the increasing incidence. In this review, our focus is on exploring the distinct imaging features of known molecular subtypes of breast cancer, underlining correlations observed in clinical practice and reported in recent studies. The imaging investigations used for assessment include screening modalities such as mammography and ultrasonography, as well as more complex investigations like MRI, which offers high sensitivity for loco-regional evaluation, and PET, which determines tumor metabolic activity using radioactive tracers. The purpose of this review is to provide a better understanding as well as a revision of the imaging differences exhibited by the molecular subtypes and histopathological types of breast cancer.

Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved as first-line therapies for breast cancer gene (BRCA)-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer. They are also effective for new and recurrent ovarian cancers that are BRCA- or homologous recombination deficiency (HRD)-positive. However, data on these mutations and PARPi use in the Middle East are limited.

To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer.

This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations, and 25 of 65 ovarian cancer patients tested for HRD. These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023. Data were summarized using descriptive statistics and compared using counts and percentages. Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria.

Among the 472 breast cancer patients, 12.1% underwent BRCA testing, and 38.5% of 65 ovarian cancer patients received HRD testing. Pathogenic mutations were found in 25.6% of the tested patients: 26.3% breast cancers had germline BRCA (gBRCA) mutations and 24.0% ovarian cancers showed HRD. Notably, 40.0% of gBRCA-positive breast cancers and 66.0% of HRD-positive ovarian cancers were Middle Eastern and Asian patients, respectively. PARPi treatment was used in 5 (33.3%) gBRCA-positive breast cancer patients as first-line therapy (n = 1; 7-months progression-free), for maintenance (n = 2; > 15-months progression-free), or at later stages due to compliance issues (n = 2). Four patients (66.6%) with HRD-positive ovarian cancer received PARPi and all remained progression-free.

Lower testing rates but higher BRCA mutations in breast cancer were found. Ethnicity reflected United Arab Emirates demographics, with breast cancer in Middle Eastern and ovarian cancer in Asian patients.

Transposable elements (TEs) and other repetitive regions have been shown to contain gene regulatory elements, including transcription factor binding sites. However, regulatory elements harbored by repeats have proven difficult to characterize using short-read sequencing assays such as ChIP-seq or ATAC-seq. Most regulatory genomics analysis pipelines discard "multimapped" reads that align equally well to multiple genomic locations. Because multimapped reads arise predominantly from repeats, current analysis pipelines fail to detect a substantial portion of regulatory events that occur in repetitive regions. To address this shortcoming, we developed Allo, a new approach to allocate multimapped reads in an efficient, accurate, and user-friendly manner. Allo combines probabilistic mapping of multimapped reads with a convolutional neural network that recognizes the read distribution features of potential peaks, offering enhanced accuracy in multimapping read assignment. Allo also provides read-level output in the form of a corrected alignment file, making it compatible with existing regulatory genomics analysis pipelines and downstream peak-finders. In a demonstration application on CTCF ChIP-seq data, we show that Allo results in the discovery of thousands of new CTCF peaks. Many of these peaks contain the expected cognate motif and/or serve as TAD boundaries. We additionally apply Allo to a diverse collection of ENCODE ChIP-seq data sets, resulting in multiple previously unidentified interactions between transcription factors and repetitive element families. Finally, we show that Allo may be particularly beneficial in identifying ChIP-seq peaks at centromeres, near segmentally duplicated genes, and in younger TEs, enabling new regulatory analyses in these regions.

Maintenance of genome stability is of paramount importance for the survival of an organism. However, genomic integrity is constantly being challenged by various endogenous and exogenous processes that damage DNA. Therefore, cells are heavily reliant on DNA repair pathways that have evolved to deal with every type of genotoxic insult that threatens to compromise genome stability. Notably, inherited mutations in genes encoding proteins involved in these protective pathways trigger the onset of disease that is driven by chromosome instability e.g. neurodevelopmental abnormalities, neurodegeneration, premature ageing, immunodeficiency and cancer development. The ability of cells to regulate the recruitment of specific DNA repair proteins to sites of DNA damage is extremely complex but is primarily mediated by protein post-translational modifications (PTMs). Ubiquitylation is one such PTM, which controls genome stability by regulating protein localisation, protein turnover, protein-protein interactions and intra-cellular signalling. Over the past two decades, numerous ubiquitin (Ub) E3 ligases have been identified to play a crucial role not only in the initiation of DNA replication and DNA damage repair but also in the efficient termination of these processes. In this review, we discuss our current understanding of how different Ub E3 ligases (RNF168, TRAIP, HUWE1, TRIP12, FANCL, BRCA1, RFWD3) function to regulate DNA repair and replication and the pathological consequences arising from inheriting deleterious mutations that compromise the Ub-dependent DNA damage response.

The incidence of thyroid cancer, one of the most common forms of endocrine cancer, is increasing rapidly worldwide in developed and developing countries. Various risk factors can increase susceptibility to thyroid cancer, but particular emphasis is put on the role of DNA repair genes, which have a significant impact on genome stability. Polymorphisms of these genes can increase the risk of developing thyroid cancer by affecting their function. In this article, we present a concise review on the most common polymorphisms of selected DNA repair genes that may influence the risk of thyroid cancer. We point out significant differences in the frequency of these polymorphisms between various populations and their potential relationship with susceptibility to the disease. A more complete understanding of these differences may lead to the development of effective prevention strategies and targeted therapies for thyroid cancer. Simultaneously, there is a need for further research on the role of polymorphisms of previously uninvestigated DNA repair genes in the context of thyroid cancer, which may contribute to filling the knowledge gaps on this subject.

Our current study reports the successful synthesis of thiolated chitosan-based nanoparticles for targeted drug delivery of 5-Fluorouracil. This process was achieved through the ionic gelation technique, aiming to improve the efficacy of the chemotherapeutic moiety by modifying the surface of the nanoparticles (NPs) with a ligand. We coated these NPs with hyaluronic acid (HA) to actively target the CD44 receptor, which is frequently overexpressed in various solid malignancies, including breast cancer. XRD, FTIR, SEM, and TEM were used for the physicochemical analysis of the NPs. These 5-Fluorouracil (5-FU) loaded NPs were evaluated on MDA-MB-231 (a triple-negative breast cell line) and MCF-10A (normal epithelial breast cells) to determine their in vitro efficacy. The developed 5-FU-loaded NPs exhibited a particle size within a favorable range (< 300 nm). The positive zeta potential of these nanoparticles facilitated their uptake by negatively charged cancer cells. Moreover, they demonstrated robust stability and achieved high encapsulation efficiency. These nanoparticles exhibited significant cytotoxicity compared to the crude drug (p < 0.05) and displayed a promising release pattern consistent with the basic diffusion model. These traits improve the pharmacokinetic profile, efficacy, and ability to precisely target these nanoparticles, offering a potentially successful anticancer treatment for breast cancer. However, additional in vivo assessments of these formulations are obligatory to confirm these findings.

The objective of this study was to identify and classify the spectrum of mutations found in the BRCA1 and BRCA2 genes associated with breast and ovarian cancer in female patients in Romania. Germline BRCA1 and BRCA2 mutations were investigated in a cohort of 616 female patients using NGS and/or MLPA methods followed by software-based data analysis and classification according to international guidelines. Out of the 616 female patients included in this study, we found that 482 patients (78.2%) did not have any mutation present in the two genes investigated; 69 patients (11.2%) had a BRCA1 mutation, 34 (5.5%) had a BRCA2 mutation, and 31 (5%) presented different type of mutations with uncertain clinical significance, moderate risk or a large mutation in the BRCA1 gene. Our investigation indicates the most common mutations in the BRCA1 and BRCA2 genes, associated with breast and ovarian cancer in the Romanian population. Our results also bring more data in support of the frequency of the c.5266 mutation in the BRCA1 gene, acknowledged in the literature as a founder mutation in Eastern Europe. We consider that the results of our study will provide necessary data regarding BRCA1 and BRCA2 mutations that would help to create a genetic database for the Romanian population.

Breast cancer is the most common cancer in women worldwide. Toxoplasma gondii (T. gondii) has shown anticancer activity in breast cancer mouse models, and exerted beneficial effect on the survival of breast cancer patients, but the mechanism was unclear.

The effect of tachyzoites of T. gondii (RH and ME49 strains) on human breast cancer cells (MCF-7 and MDA-MB-231 cells) proliferation and migration was assessed using cell growth curve and wound healing assays. Dual RNA-seq was performed for T. gondii-infected and non-infected cells to determine the differentially expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction Networks analysis (PPI) were performed to explore the related signaling pathway and hub genes. Hub genes were validated using the Kaplan-Meier plotter database, and Pathogen Host Interaction (PHI-base) database. The results were verified by qRT-PCR.

The tachyzoites of T. gondii decreased the expression of Ki67 and increased the expression of E-cadherin, resulting in suppressing the proliferation and migration of infected human breast cancer cells. The inhibitory effect of T. gondii on breast cancer cells showed a significant dose-response relationship. Compared with the control group, 2321 genes were transcriptionally regulated in MCF-7 cells infected with T. gondii, while 169 genes were transcriptionally regulated in infected MDA-MB-231 cells. Among these genes, 698 genes in infected MCF-7 cells and 67 genes in infected MDA-MB-231 cells were validated by the publicly available database. GO and KEGG analyses suggested that several pathways were involved in anticancer function of T. gondii, such as ribosome, interleukin-17 signaling, coronavirus disease pathway, and breast cancer pathway. BRCA1, MYC and IL-6 were identified as the top three hub genes in infected-breast cancer cells based on the connectivity of PPI analysis. In addition, after interacting with breast cancer cells, the expression of ROP16 and ROP18 in T. gondii increased, while the expression of crt, TgIST, GRA15, GRA24 and MIC13 decreased.

T. gondii transcriptionally regulates several signaling pathways by altering the hub genes such as BRCA1, MYC and IL-6, which can inhibit the breast tumor growth and migration, hinting at a potential therapeutic strategy.

Studying gene regulatory networks associated with cancer provides valuable insights for therapeutic purposes, given that cancer is fundamentally a genetic disease. However, as the number of genes in the system increases, the complexity arising from the interconnections between network components grows exponentially. In this study, using Boolean logic to adjust the existing relationships between network components has facilitated simplifying the modeling process, enabling the generation of attractors that represent cell phenotypes based on breast cancer RNA-seq data. A key therapeutic objective is to guide cells, through targeted interventions, to transition from the current cancer attractor to a physiologically distinct attractor unrelated to cancer. To achieve this, we developed a computational method that identifies network nodes whose inhibition can facilitate the desired transition from one tumor attractor to another associated with apoptosis, leveraging transcriptomic data from cell lines. To validate the model, we utilized previously published in vitro experiments where the downregulation of specific proteins resulted in cell growth arrest and death of a breast cancer cell line. The method proposed in this manuscript combines diverse data sources, conducts structural network analysis, and incorporates relevant biological knowledge on apoptosis in cancer cells. This comprehensive approach aims to identify potential targets of significance for personalized medicine.

This study evaluated the cost effectiveness of adjuvant olaparib versus watch and wait (WaW) in patients with germline breast cancer susceptibility gene 1/2 (gBRCA1/2)-mutated, high-risk, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC), previously treated with neoadjuvant or adjuvant chemotherapy, from a Swedish healthcare perspective.

A five-state (invasive disease-free survival [IDFS], non-metastatic breast cancer [non-mBC], early-onset mBC, late-onset mBC, death) semi-Markov state transition model with a lifetime horizon was developed. Transition probabilities were informed by data from the Phase III OlympiA trial, supplemented with data from additional studies in BRCA-mutated, HER2-negative mBC. Health state utilities were derived via mapping of OlympiA data and supplemented by literature estimates. Treatment, adverse events and other medical costs were extracted from publicly available Swedish sources. Incremental cost per life-year (LY) and quality-adjusted life-year (QALY) gained were estimated. Costs and outcomes were discounted at 3% annually. One-way deterministic and probabilistic sensitivity analyses (PSA) were conducted.

Over a lifetime horizon, adjuvant olaparib was associated with an additional 1.50 LYs and 1.22 QALYs, and incremental cost of 471,156 Swedish krona (SEK) versus WaW (discounted). The resulting ICER was 385,183SEK per QALY gained for olaparib versus WaW. ICERs remained below 1,000,000SEK across a range of scenarios, and were consistent across subgroups (hormone receptor [HR]-positive/HER2-negative and triple-negative breast cancer [TNBC]). In PSA, the probability of olaparib being cost effective at 1,000,000SEK per QALY was 99.8%.

At list price, adjuvant olaparib is a cost-effective alternative to WaW in patients with gBRCA1/2-mutated, high-risk, HER2-negative eBC in Sweden.

Prioritizing candidate drugs based on genome-wide expression data is an emerging approach in systems pharmacology due to its holistic perspective for preclinical drug evaluation. In the current study, a network-based approach was proposed and applied to prioritize plant polyphenols and identify potential drug combinations in breast cancer. We focused on MEK5/ERK5 signalling pathway genes, a recently identified potential drug target in cancer with roles spanning major carcinogenesis processes.

By constructing and identifying perturbed protein-protein interaction networks for luminal A breast cancer, plant polyphenols and drugs from transcriptome data, we first demonstrated their systemic effects on the MEK5/ERK5 signalling pathway. Subsequently, we applied a pathway-specific network pharmacology pipeline to prioritize plant polyphenols and potential drug combinations for use in breast cancer. Our analysis prioritized genistein among plant polyphenols. Drug combination simulations predicted several FDA-approved drugs in breast cancer with well-established pharmacology as candidates for target network synergistic combination with genistein. This study also highlights the concept of target network enhancer drugs, with drugs previously not well characterised in breast cancer being prioritized for use in the MEK5/ERK5 pathway in breast cancer.

This study proposes a computational framework for drug prioritization and combination with the MEK5/ERK5 signaling pathway in breast cancer. The method is flexible and provides the scientific community with a robust method that can be applied to other complex diseases.

Known as a diverse collection of neoplastic diseases, breast cancer (BC) can be hyperbolically characterized as a dynamic pseudo-organ, a living organism able to build a complex, open, hierarchically organized, self-sustainable, and self-renewable tumor system, a population, a species, a local community, a biocenosis, or an evolving dynamical ecosystem (i.e., immune or metabolic ecosystem) that emphasizes both developmental continuity and spatio-temporal change. Moreover, a cancer cell community, also known as an oncobiota, has been described as non-sexually reproducing species, as well as a migratory or invasive species that expresses intelligent behavior, or an endangered or parasite species that fights to survive, to optimize its features inside the host's ecosystem, or that is able to exploit or to disrupt its host circadian cycle for improving the own proliferation and spreading. BC tumorigenesis has also been compared with the early embryo and placenta development that may suggest new strategies for research and therapy. Furthermore, BC has also been characterized as an environmental disease or as an ecological disorder. Many mechanisms of cancer progression have been explained by principles of ecology, developmental biology, and evolutionary paradigms. Many authors have discussed ecological, developmental, and evolutionary strategies for more successful anti-cancer therapies, or for understanding the ecological, developmental, and evolutionary bases of BC exploitable vulnerabilities. Herein, we used the integrated framework of three well known ecological theories: the Bronfenbrenner's theory of human development, the Vannote's River Continuum Concept (RCC), and the Ecological Evolutionary Developmental Biology (Eco-Evo-Devo) theory, to explain and understand several eco-evo-devo-based principles that govern BC progression. Multi-omics fields, taken together as onco-breastomics, offer better opportunities to integrate, analyze, and interpret large amounts of complex heterogeneous data, such as various and big-omics data obtained by multiple investigative modalities, for understanding the eco-evo-devo-based principles that drive BC progression and treatment. These integrative eco-evo-devo theories can help clinicians better diagnose and treat BC, for example, by using non-invasive biomarkers in liquid-biopsies that have emerged from integrated omics-based data that accurately reflect the biomolecular landscape of the primary tumor in order to avoid mutilating preventive surgery, like bilateral mastectomy. From the perspective of preventive, personalized, and participatory medicine, these hypotheses may help patients to think about this disease as a process governed by natural rules, to understand the possible causes of the disease, and to gain control on their own health.