Prospective Study of Homologous Recombination Repair Gene Mutation Prevalence in Patients With Advanced Prostate Cancer From Latin America: Challenges and Future Approaches.

PURPOSE: The prevalence of homologous recombination repair gene mutations (HRRm) in patients with metastatic castration-resistant prostate cancer (mCRPC) in Latin America and the Caribbean (LAC) is unknown. Prevalence of homologous Recombination repair (HRR) gene mutatiOns in patientS with metastatic castration resistant ProstatE Cancer in LaTin America (PROSPECT) aimed to determine this prevalence and to describe the demographic and clinical characteristics of the participants. MATERIALS AND METHODS: This was a prospective, cross-sectional, multicenter study across 11 cancer centers in seven LAC countries. After informed consent, all eligible participants underwent genomic testing by provided blood samples for germline HRR testing; they also provided PC tissue blocks if available for somatic HRR testing. RESULTS: Between April 2021 and April 2022, 387 patients (median age, 70 years [49-89], 94.3% Eastern Cooperative Oncology Group 0-1) with mCRPC were enrolled in the study. Almost 40% of them had a family history of cancer, and the overall time from their initial PC and mCRPC diagnosis was 3 years and 1 year, respectively. The overall prevalence of germline HRRm was 4.2%. The mutations detected included the genes CHEK2 (n = 4, 1%), ATM (n = 3, 0.8%), BRCA2 (n = 3, 0.8%), BRIP1 (n = 2, 0.5%), RAD51B (n = 2, 0.5%), BRCA1 (n = 1, 0.3%), and MRE11 (n = 1, 0.3%). The prevalence of somatic HRRm could not be assessed because of high HRR testing failure rates (79%, 199/251) associated with insufficient DNA, absence of tumor cells, and poor-quality DNA. CONCLUSION: Despite the study's limitations, to our knowledge, PROSPECT was the first attempt to describe the prevalence of HRRm in patients with PC from LAC. Notably, the germline HRRm prevalence in this study was inferior to that observed in North American and European populations. The somatic HRR testing barriers identified are being addressed by several projects to improve access to HRR testing and biomarker-based therapies in LAC.

Generation of a Human Deafness Sheep Model Using the CRISPR/Cas System.

CRISPR/Cas9 system is a promising method for the generation of human disease models by genome editing in non-conventional experimental animals. Medium/large-sized animals like sheep have several advantages to study human diseases and medicine. Here, we present a protocol that describes the generation of an otoferlin edited sheep model via CRISPR-assisted single-stranded oligodinucleotide-mediated Homology-Directed Repair (HDR), through direct cytoplasmic microinjection in in vitro produced zygotes.Otoferlin is a protein expressed in the cochlear inner hair cells, with different mutations at the OTOF gene being the major cause of nonsyndromic recessive auditory neuropathy spectrum disorder in humans. By using this protocol, we reported for the first time an OTOF KI model in sheep with 17.8% edited lambs showing indel mutations, and 61.5% of them bearing knock-in mutations by HDR . The reported method establishes the bases to produce a deafness model to test novel therapies in human disorders related to OTOF mutations.

Interactions between miRNAs and Double-Strand Breaks DNA Repair Genes, Pursuing a Fine-Tuning of Repair.

The repair of DNA damage is a crucial process for the correct maintenance of genetic information, thus, allowing the proper functioning of cells. Among the different types of lesions occurring in DNA, double-strand breaks (DSBs) are considered the most harmful type of lesion, which can result in significant loss of genetic information, leading to diseases, such as cancer. DSB repair occurs through two main mechanisms, called non-homologous end joining (NHEJ) and homologous recombination repair (HRR). There is evidence showing that miRNAs play an important role in the regulation of genes acting in NHEJ and HRR mechanisms, either through direct complementary binding to mRNA targets, thus, repressing translation, or by targeting other genes involved in the transcription and activity of DSB repair genes. Therefore, alteration of miRNA expression has an impact on the ability of cells to repair DSBs, which, in turn, affects cancer therapy sensitivity. This latter gives account of the importance of miRNAs as regulators of NHEJ and HRR and places them as a promising target to improve cancer therapy. Here, we review recent reports demonstrating an association between miRNAs and genes involved in NHEJ and HRR. We employed the Web of Science search query TS ("gene official symbol/gene aliases*" AND "miRNA/microRNA/miR-") and focused on articles published in the last decade, between 2010 and 2021. We also performed a data analysis to represent miRNA-mRNA validated interactions from TarBase v.8, in order to offer an updated overview about the role of miRNAs as regulators of DSB repair.

PALB2 Variants: Protein Domains and Cancer Susceptibility.

Since its discovery, partner and localizer of breast cancer 2 (BRCA2) (PALB2) has emerged as a major tumor suppressor gene linked to breast cancer (BC), pancreatic cancer (PC), and ovarian cancer (OC) susceptibility. Its protein product plays a pivotal role in the maintenance of genome integrity. Here we discuss the first functional evaluation of a large set of PALB2 missense variants of uncertain significance (VUSs). Assessment of 136 VUSs interrogating a range of PALB2 biological functions resulted in the identification of 15 variants with consistent loss of function across different assays. All loss-of-function variants are located at the PALB2 coiled coil (CC) or at the WD40 domain, highlighting the importance of modular domains mechanistically involved in the DNA damage response (DDR) and pinpointing their roles in tumor suppression.

NUCKS1 promotes RAD54 activity in homologous recombination DNA repair.

NUCKS1 (nuclear ubiquitous casein kinase and cyclin-dependent kinase substrate 1) is a chromatin-associated, vertebrate-specific, and multifunctional protein with a role in DNA damage signaling and repair. Previously, we have shown that NUCKS1 helps maintain homologous recombination (HR) DNA repair in human cells and functions as a tumor suppressor in mice. However, the mechanisms by which NUCKS1 positively impacts these processes had remained unclear. Here, we show that NUCKS1 physically and functionally interacts with the DNA motor protein RAD54. Upon exposure of human cells to DNA-damaging agents, NUCKS1 controls the resolution of RAD54 foci. In unperturbed cells, NUCKS1 prevents RAD54's inappropriate engagement with RAD51AP1. In vitro, NUCKS1 stimulates the ATPase activity of RAD54 and the RAD51-RAD54-mediated strand invasion step during displacement loop formation. Taken together, our data demonstrate that the NUCKS1 protein is an important new regulator of the spatiotemporal events in HR.

Otoferlin gene editing in sheep via CRISPR-assisted ssODN-mediated Homology Directed Repair.

Different mutations of the OTOF gene, encoding for otoferlin protein expressed in the cochlear inner hair cells, induces a form of deafness that is the major cause of nonsyndromic recessive auditory neuropathy spectrum disorder in humans. We report the generation of the first large animal model of OTOF mutations using the CRISPR system associated with different Cas9 components (mRNA or protein) assisted by single strand oligodeoxynucleotides (ssODN) to induce homology-directed repair (HDR). Zygote microinjection was performed with two sgRNA targeting exon 5 and 6 associated to Cas9 mRNA or protein (RNP) at different concentrations in a mix with an ssODN template targeting HDR in exon 5 containing two STOP sequences. A total of 73 lambs were born, 13 showing indel mutations (17.8%), 8 of which (61.5%) had knock-in mutations by HDR. Higher concentrations of Cas9-RNP induced targeted mutations more effectively, but negatively affected embryo survival and pregnancy rate. This study reports by the first time the generation of OTOF disrupted sheep, which may allow better understanding and development of new therapies for human deafness related to genetic disorders. These results support the use of CRISPR/Cas system assisted by ssODN as an effective tool for gene editing in livestock.

Measuring the Contributions of the Rho Pathway to the DNA Damage Response in Tumor Epithelial Cells.

Actin polymerization, actomyosin ring contraction, and stress fiber formation are examples of relevant actions of the RhoA/B/C pathway as GTPases that regulate the cytoskeleton. However, open questions that remain to be addressed are whether this pathway and/or downstream components protect against or facilitate the formation of DNA double-strand breaks, the most lethal form of DNA damage in cells. Genotoxic drugs are radiomimetic and/or chemotherapeutic agents that are currently used for cancer treatments and are associated with specific methodologies; thus, these compounds should represent good tools to answer these questions. In this chapter, we describe two methods, the alkaline comet assay and homologous/nonhomologous recombination assays, to investigate the mechanism by which the Rho pathway modulates the repair of DNA breaks in tumor epithelial cell lines.

Recruitment kinetics of the homologous recombination pathway in procyclic forms of Trypanosoma brucei after ionizing radiation treatment.

One of the most important mechanisms for repairing double-strand breaks (DSBs) in model eukaryotes is homologous recombination (HR). Although the genes involved in HR have been found in Trypanosoma brucei and studies have identified some of the proteins that participate in this HR pathway, the recruitment kinetics of the HR machinery onto DNA during DSB repair have not been clearly elucidated in this organism. Using immunofluorescence, protein DNA-bound assays, and DNA content analysis, we established the recruitment kinetics of the HR pathway in response to the DSBs generated by ionizing radiation (IR) in procyclic forms of T. brucei. These kinetics involved the phosphorylation of histone H2A and the sequential recruitment of the essential HR players Exo1, RPA, and Rad51. The process of DSB repair took approximately 5.5 hours. We found that DSBs led to a decline in the G2/M phase after IR treatment, concomitant with cell cycle arrest in the G1/S phase. This finding suggests that HR repairs DSBs faster than the other possible DSB repair processes that act during the G1/S transition. Taken together, these data suggest that the interplay between DNA damage detection and HR machinery recruitment is finely coordinated, allowing these parasites to repair DNA rapidly after DSBs during the late S/G2 proficient phases.

The Role of PALB2 in the DNA Damage Response and Cancer Predisposition.

The deoxyribonucleic acid (DNA) damage response (DDR) is a major feature in the maintenance of genome integrity and in the suppression of tumorigenesis. PALB2 (Partner and Localizer of Breast Cancer 2 (BRCA2)) plays an important role in maintaining genome integrity through its role in the Fanconi anemia (FA) and homologous recombination (HR) DNA repair pathways. Since its identification as a BRCA2 interacting partner, PALB2 has emerged as a pivotal tumor suppressor protein associated to hereditary cancer susceptibility to breast and pancreatic cancers. In this review, we discuss how other DDR proteins (such as the kinases Ataxia Telangiectasia Mutated (ATM) and ATM- and Rad3-Related (ATR), mediators BRCA1 (Breast Cancer 1)/BRCA2 and effectors RAD51/DNA Polymerase η (Polη) interact with PALB2 to orchestrate DNA repair. We also examine the involvement of PALB2 mutations in the predisposition to cancer and the role of PALB2 in stimulating error-free DNA repair through the FA/HR pathway.

Alteração da via da recombinação homóloga de reparo de DNA no câncer epitelial de ovário / Homologous recombination deficiency in ovarian carcinoma

Justificativa:Os carcinomas de ovário apresentam deficiência da via da recombinação homóloga de reparo de DNA em aproximadamente 50% dos casos, em 15 a 20% dos casos atribuída a mutações germinativas em BRCA1 ou BRCA2. Tumores com mutações germinativas em BRCA1 ou BRCA2 são mais sensíveis aos tratamentos com inibidores de PARP e com esquemas quimioterápicos baseados em platina. O papel de outras alterações da via da recombinação homóloga na sensibilidade a essas modalidades de tratamento bem como a forma de identificar os tumores com deficiência dessa via ainda não estão definidos. Escores avaliando o perfil de alterações estruturais genômicas causadas especificamente por deficiência da via da recombinação homóloga têm sido estudados como potenciais marcadores da deficiência desta via. Nosso objetivo foi caracterizar uma coorte de pacientes com carcinoma de ovário quanto à deficiência da via da recombinação homóloga utilizando escores calculados a partir das alterações do número de cópias genômicas e de perdas de heterozigose e avaliar o papel destes escores na identificação de pacientes com sensibilidade prolongada à platina. Métodos: Selecionamos uma coorte de 31 pacientes com carcinoma de ovário com recidiva classificada clinicamente com platina resistente e que foram reexpostas ao tratamento com quimioterapia baseada em platina. Amostras de tumores armazenados em parafina de 14 pacientes foram submetidas ao ensaio ONCOSCAN para avaliação de alterações de números de cópias, perda de heterozigose e identificação de mutações específicas em 9 genes relacionados a neoplasias. A partir destes dados caracterizamos os escores de Telomeric Allelic Imbalance (TAI), escore de perda de heterozigose (cnLOH+L) escore de Large Scale Transition (LST) e escore de deficiência da recombinação homóloga (HRD) em cada tumor e avaliamos a sua associação com a taxa de resposta à quimioterapia, sobrevida global e fatores clínico patológicos. Resultados: Na coorte de 31 pacientes, DNA foi extraído de 28 amostras e 15 amostras de 14 pacientes foram analisadas de forma efetiva. Na maioria dos casos encontramos o padrão esperado de grande instabilidade genômica com diversas regiões de ganhos e perdas do genoma e regiões de perda de heterozigose. Todos os casos analisados mostraram cnLOH ou delLOH no cromossomo 17, 12 de 14 pacientes apresentaram cnLOH ou delLOH no braço longo do cromossomo 13 e o cromossomo 22 apresentou perdas ou ganhos na maioria dos casos. Mutação em TP53 foi encontrada em 2 casos, mutação em NRAS em 2 casos, e um caso com mutação em TP53apresentou mutação em PTEN associada a deleção da região do PTEN. A mediana dos escores foi de 19,5 para TAI, 12,5 para cnLOH+L, 26,0 para LST e 6,3 para HRD. Levando-se em conta os escores com pontos de corte previamente definidos na literatura encontramos 10 de 14 (escore cnLOH+L) e 9 de 14 (escore LST) pacientes com tumores com escores altos sugerindo deficiência da via da recombinação homóloga. Tanto a coorte como um todo quanto as 14 pacientes submetidas à análise molecular apresentaram taxa de resposta acima do esperado sendo 16 de 31 pacientes (51,6%) e 7 de 14 pacientes (50,0) respectivamente. Não houve diferença estatisticamente significativa entre as taxas de resposta das pacientes de com escores altos versus baixos, embora 6 de 10 pacientes com escore cnLOH+L elevado tenham apresentado resposta e 1 de 4 pacientes com escore cnLOH+L baixo tenham apresentado resposta e 6 de 9 pacientes com escore LST elevado tenham apresentado resposta e 1 de 5 pacientes com escore LST baixo tenham apresentado resposta. Numericamente os escores cnLOH+L, LST e HDR foram mais altos nas pacientes que responderam quando comparados com os escores das pacientes que não responderam, com medianas deTAI = 19,0 vs 24,0, TAIm = 16,0 vs 19,0, cnLOH+L 13 vs 12, LST = 28,0 vs 18,0, LSTm = -4,0 vs -20,0, HRD 8,7 vs 0,3 para respondedoras versus não respondedoras. Essa diferença não foi estatisticamente significativa. A sobrevida global mediana foi 13,4 meses desde o inicio do tratamento de reexposição à platina e não houve diferença de acordo com os valores dos escores. Dentre os fatores clinicopatológicos a presença de história familiar de câncer de mama ou ovário ou a história pessoal de câncer de mama foi o único fator associado a uma maior taxa de resposta. Os tumores primários apresentaram escore TAI mais elevado que os tumores coletados no momento da recidiva e comparando duas amostras de uma mesma paciente houve diferença na classificação da deficiência da via da recombinação homóloga de acordo com os escores cnLOH+L e LST. Conclusões: Os escores de deficiência da via da recombinação homóloga se mostraram potenciais marcadores de resposta à reexposição à platina no cenário de doença platina resistente, necessitando melhor definição dos pontos de corte e do impacto da heterogeneidade tumoral e da necessidade de avaliação do material coletado no momento da recidiva. História familiar positiva é um fator clínico capaz de identificar pacientes com mais chance de resposta á reexposição á platina. Nossos dados fortalecem a hipótese da contribuição de mutações em PTEN para o desenvolvimento de deficiência da via da recombinação homóloga e o papel das mutações de NRAS nos carcinomas serosos de ovário.

Background: Homologous recombination deficiency s presente in up to 50% of ovarian carcinomas, in 15 to 20% due to germline BRCA1 or BRCA2 mutations. BRCA mutated tumors are more sensitive to PARP inhibitors and platinum based chemotherapy. The role of other homologous recombination mechanisms on PARP inhibitors and platinum sensitivity as well as the methods to identify homologous recombination deficiency is not clear yet. Scores evaluating structural genomic abnormalities caused specifically by homologous recombination deficiency have been studied as markers of deficiency of this DNA repair pathway. The main objective of the present study was to characterize a cohort of ovarian cancer patients regarding homologous recombination deficiency using scores based on copy number alterations and loss of heterozygosity and to evaluate the impact of these scores in prolonged platinum sensitivity. Methods: We selected a cohort of 31 ovarian cancer patients with platinum resistant recurrence reexposed to platinum based chemotherapy. Paraffin embedded tumor samples from 14 patients were analyzed through ONCOSCAN assay for copy number alterations, loss of heterozygosity and specific point mutations in 9 cancer related genes. Based on these alterations we calculated the scores Telomeric Allelic Imbalance (TAI), loss of heterozygosity score (cnLOH+L) Large Scale Transition score (LST) and homologous recombination deficiency score (HRD) for each tumor sample and tested their association to response rate to platinum rechallenge, overall survival and to the clinical pathologic factors. Results: From the cohort of 31 patients, DNA was extracted from 28 samples and 15 samples from 14 patients were effectively analyzed. Most cases presented the expected high genomic instability pattern with lots of genomic losses, genomic gains and loss of heterozygosity segments. All cases showed cnLOH or delLOH in chromosome 17, 12 of 14 patients showed cnLOH or delLOH in the long arm of chromosome 13, and chromosome 22 presented losses or gains in most of cases.TP53 mutations were present in 2 cases, NRAS mutations in 2 cases, and one patient with TP53 mutation showed also a PTEN mutation together with a genomic loss in PTEN region. Median scores were 19,5 for TAI, 12,5 for cnLOH+L, 26,0 for LST and 6,3 for HRD. Considering previously literature defined cutoffs we found 10 out of 14 (for cnLOH+L score) and 9 out of 14 (for LST score) patients with tumors with high scores suggesting homologous recombination deficiency. In the cohort of 31 patients 16 had response to platinum reexposition and in the cohort of 14 patients analyzed by ONCOSCAN assay 7 patients had response. There was no statistically significant difference between response rates for high versus low scores, even though 6 out of 10 patient with high cnLOH+L score while 1 out of 4 patients with low cnLOH+L score had response and 6 out of 9 patient with high cnLOH+L score while 1 out of 5 patients with low cnLOH+L score had response. Numerically, the scores cnLOH+L, LST and HDR were higher in patients with response to treatment compared to those without a response, with medians of TAI = 19,0 vs 24,0, TAIm = 16,0 vs 19,0, cnLOH+L 13 vs 12, LST = 28,0 vs 18,0, LSTm = -4,0 vs -20,0, HRD 8,7 vs 0,3 for responders versus non responders respectively. These differences were not statistically significant. Median overall survival was 13,4 months from the beginning of platinum rechallenge and there was no difference in survival according to scores. Among clinical pathologic factors, family history of breast or ovarian cancer or personal history of breast cancer was associated to a higher response rate to platinum rechallenge. Primary tumors had a higher TAI score compared to recurrent tumors and comparing two different samples from the same patient there was divergence on the homologous recombination deficiency classification according to cnLOH+L and LST scores. Conclusions: Homologous recombination deficiency scores showed to be potential markers of response to platinum rechallenge in the platinum resistant setting. It is still necessary to clarify the best cutoffs for each score, the impact of tumor heterogeneity and the need of tumor samples to be collected in the moment of treatment. Positive family history is a clinical factor predictvie of platinum rechallenge response. Our data support the hypothesis of a role for PTEN in homologous recombination deficiency as well as a role of NRAS mutations in ovarian serous carcinomas.

Assessment of adherence to the guidelines for the management of nausea and vomiting induced by chemotherapy / Avaliação da aderência à diretriz de cuidados para náuseas e vômitos induzidos por quimioterapia

ABSTRACT Objective: To assess adherence of the prescribing physicians in a private cancer care center to the American Society of Clinical Oncology guideline for antiemetic prophylaxis, in the first cycle of antineoplastic chemotherapy. Methods: A total of 139 chemotherapy regimens, of 105 patients, were evaluated retrospectively from 2011 to 2013. Results: We observed 78% of non-adherence to the guideline rate. The main disagreements with the directive were the prescription of higher doses of dexamethasone and excessive use of 5-HT3 antagonist for low risk emetogenic chemotherapy regimens. On univariate analysis, hematological malignancies (p=0.005), the use of two or more chemotherapy (p=0.05) and high emetogenic risk regimes (p=0.012) were factors statistically associated with greater adherence to guidelines. Treatment based on paclitaxel was the only significant risk factor for non-adherence (p=0.02). By multivariate analysis, the chemotherapy of high emetogenic risk most correlated with adherence to guideline (p=0.05). Conclusion: We concluded that the adherence to guidelines is greater if the chemotherapy regime has high emetogenic risk. Educational efforts should focus more intensely on the management of chemotherapy regimens with low and moderate emetogenic potential. Perhaps the development of a computer generated reminder may improve the adherence to guidelines. .

RESUMO Objetivo: Avaliar a adesão dos médicos prescritores, de um centro privado especializado em oncologia, à diretriz de antiêmese profilática da American Society of Clinical Oncology, no primeiro ciclo de quimioterapia antineoplásica. Métodos: Foram avaliados retrospectivamente 139 esquemas de quimioterapia, de 105 pacientes, tratados no período de 2011 a 2013. Resultados: Foram observados 78% de taxa de não adesão à diretriz. As principais discordâncias com a diretriz foram prescrição de doses mais elevadas de dexametasona e uso excessivo de antagonista 5-HT3 para regimes de quimioterapia de risco emetogênico baixo. Pela análise univariada, malignidades hematológicas (p=0,005), uso de dois ou mais quimioterápicos (p=0,05) e regimes de alto risco emetogênico (p=0,012) foram fatores estatisticamente associados a maior adesão à diretriz. O tratamento baseado em paclitaxel foi o único fator estatisticamente significativo para a não adesão (p=0,02). Pela análise multivariada, a quimioterapia de alto risco emetogênico apresentou maior correlação com a adesão à diretriz (p=0,05). Conclusão: Houve maior aderência para a quimioterapia de alto risco emetogênico. Esforços educacionais devem se concentrar mais intensamente na gestão de regimes de quimioterapia com potencial emetogênico baixo e moderado. Talvez o desenvolvimento de lembretes gerados por sistemas informatizados possa melhorar a aderência à diretriz. .

The distribution of recombination repair genes is linked to information content in bacteria.

The concept of a 'proteomic constraint' proposes that the information content of the proteome exerts a selective pressure to reduce mutation rates, implying that larger proteomes produce a greater selective pressure to evolve or maintain DNA repair, resulting in a decrease in mutational load. Here, the distribution of 21 recombination repair genes was characterized across 900 bacterial genomes. Consistent with prediction, the presence of 17 genes correlated with proteome size. Intracellular bacteria were marked by a pervasive absence of recombination repair genes, consistent with their small proteome sizes, but also consistent with alternative explanations that reduced effective population size or lack of recombination may decrease selection pressure. However, when only non-intracellular bacteria were examined, the relationship between proteome size and gene presence was maintained. In addition, the more widely distributed (i.e. conserved) a gene, the smaller the average size of the proteomes from which it was absent. Together, these observations are consistent with the operation of a proteomic constraint on DNA repair. Lastly, a correlation between gene absence and genome AT content was shown, indicating a link between absence of DNA repair and elevated genome AT content.

Relationship between B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) and homologous recombination regulatory genes in invasive ductal breast carcinomas.

B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) is a Polycomb group protein that is able to induce telomerase activity, enabling the immortalization of epithelial cells. Immortalized cells are more susceptible to double-strand breaks (DSB), which are subsequently repaired by homologous recombination (HR). BRCA1 is among the HR regulatory genes involved in the response to DNA damage associated with the RAD51 protein, which accumulates in DNA damage foci after signaling H2AX, another important marker of DNA damage. Topoisomerase IIIß (topoIIIß) removes HR intermediates before chromosomal segregation, preventing damage to cellular DNA structure. In breast carcinomas positive for BMI-1 the role of proteins involved in HR remains to be investigated. The aim of this study was to evaluate the association between BMI-1 and homologous recombination proteins. Using tissue microarrays containing 239 cases of primary breast tumors, the expression of Bmi-1, BRCA-1, H2AX, Rad51, p53, Ki-67, topoIIIß, estrogen receptors (ER), progesterone receptors (PR), and HER-2 was analyzed by immunohistochemistry. We observed high Bmi-1 expression in 66 cases (27.6%). Immunohistochemical overexpression of BMI-1 was related to ER (p=0.004), PR (p<0.001), Ki-67 (p<0.001), p53 (p=0.003), BRCA-1 (p= 0.003), H2AX (p=0.024) and topoIIIß (p<0,001). Our results show a relationship between the expression of BMI-1 and HR regulatory genes, suggesting that Bmi-1 overexpression might be an important event in HR regulation. However, further studies are necessary to understand the mechanisms in which Bmi-1 could regulate HR pathways in invasive ductal breast carcinomas.