Pesticide exposure and increased breast cancer risk in women population studies.

Pesticide exposure is emerging as a risk factor for various human diseases. Breast cancer (BC) is a multifactorial disease with known genetic and non-genetic risk factors. Most BC cases are attibutable to non-genetic risk factors, with a history of adverse environmental exposures playing a significant role. Pesticide exposure can occur at higher levels in female populations participating in rural activities such as spraying of pesticides in the field, unprotected handling of pesticides at home, and washing of contaminated clothes. Exposure can also be significant in the drinking water of certain populations. Here, we reviewed the literature on women's exposure to pesticides and the risk of BC. We summarize the main links between pesticide exposure and BC and discuss the role of dose and exposure context, as well as potential mechanisms of toxicity. Overall, reports reviewed here have documented stronger associations between higher levels of exposure and BC risk, including documenting direct and acute pesticide exposure in certain female populations. However, discrepancies among studies regarding dose and mode of exposure may result in misunderstandings about the risks posed by pesticide exposure. Plausible mechanisms linking pesticides to breast cancer risk include their impacts as endocrine disruptors, as well as their roles as genotoxic agents, and modulators of the epigenome. Besides establishing links between pesticide exposure and breast cancer, the literature also highlights the critical need to understand the routes and doses of women's exposure to pesticides and the specific associations and mechanisms that are determinants of disease etiology and prognosis.

Transcriptome of bone marrow-Derived stem cells reveals new inflammatory mediators related to increased survival in patients with multiple myeloma.

Although multiple myeloma (MM) is a neoplasm that leads affected individuals to death, little is known about why some patients survive much longer than others. In this context, we investigated the transcriptomic profile of bone marrow hematopoietic stem cells obtained from MM patients and compared the clinical outcomes of death and survival six months after bone marrow transplantation. The leukapheresis products of 39 patients with MM eligible for autologous transplantation were collected and analyzed. After extraction, the RNA was analyzed using the GeneChip Human Exon 1.0 Array method. The transcriptome profile was analyzed in silico, and the differentially expressed signaling pathways of interest were validated. The results showed a difference in the expression of inflammation-related genes, immune response processes, and the oxidative stress pathway. The in silico study also pointed out the involvement of the NFκB transcription factor in the possible modulation of these genes. We chose to validate molecules participating in these processes, including the cytokines TNF-α, IFN-γ, and TGF-ß1; in addition, we measured the levels of oxidative stress mediators (pro-oxidant profile and the total antioxidant capacity). TNF-α levels were significantly reduced in patients who died and were over 50 years old at diagnosis, as well as in patients with plasmacytoma. Increased TNF-α was detected in patients with very high levels of ß2-microglobulin. IFN-γ reduction was observed in patients with a complete response to treatment compared to those with a very good response. Patients with plasmacytoma who died also had an increased pro-oxidant profile. These data show the profile of inflammatory response markers that are altered in patients with MM who die quickly and serve as a basis for the development of future studies of markers to predict better survival in this disease.

3,3',5,5'-Tetramethoxybiphenyl-4,4'diol triggers oxidative stress, metabolic changes, and apoptosis-like process by reducing the PI3K/AKT/NF-κB pathway in the NCI-H460 lung cancer cell line.

Lung cancer is one of the leading causes of cancer-related deaths in men and women worldwide. Current treatments have limited efficacy, cause significant side effects, and cells can develop drug resistance. New therapeutic strategies are needed to discover alternative anticancer agents with high efficacy and low-toxicity. TMBP, a biphenyl obtained by laccase-biotransformation of 2,6-dimethoxyphenol, possesses antitumor activity against A549 adenocarcinoma cells. Without causing damage to sheep erythrocytes and mouse peritoneal macrophages of BALB/c mice. In addition to being classified as a good oral drug according to in-silico studies. This study evaluated the in-vitro cytotoxic effect of TMBP on lung-cancer cell-line NCI-H460 and reports mechanisms on immunomodulation and cell death. TMBP treatment (12.5-200 µM) inhibited cell proliferation at 24, 48, and 72 h. After 24-h treatment, TMBP at IC50 (154 µM) induced various morphological and ultrastructural changes in NCI-H460, reduced migration and immunofluorescence staining of N-cadherin and ß-catenin, induced increased reactive oxygen species and nitric oxide with reduced superoxide radical-anion, increased superoxide dismutase activity and reduced glutathione reductase. Treatment also caused metabolic stress, reduced glucose-uptake, intracellular lactate dehydrogenase and lactate levels, mitochondrial depolarization, increased lipid droplets, and autophagic vacuoles. TMBP induced cell-cycle arrest in the G2/M phase, death by apoptosis, increased caspase-3/7, and reduced STAT-3 immunofluorescence staining. The anticancer effect was accompanied by decreasing PI3K, AKT, ARG-1, and NF-κB levels, and increasing iNOS. These results suggest its potential as a candidate for use in future lung anticancer drug design studies.

Occupational exposure to pesticides dysregulates systemic Th1/Th2/Th17 cytokines and correlates with poor clinical outcomes in breast cancer patients.

Pesticides are compounds known to cause immunetoxicity in exposed individuals, which have a potential to substantially modify the prognosis of pathologies dependent on an efficient immune response, such as breast cancer. In this context, we examined the circulating cytokine profile of Th1/Th2/Th17 patterns in women occupationally exposed to pesticides and their correlation with worse prognostic outcomes. Peripheral blood samples were collected from 187 rural working women with breast cancer, occupationally exposed or not to pesticides, to quantify the levels of cytokines IL-1ß, IL-12, IL-4, IL-17-A, and TNF -α. Data on the disease profile and clinical outcomes were collected through medical follow-up. IL-12 was reduced in exposed women with tumors larger than 2 cm and in those with lymph node metastases. Significantly reduced levels of IL-17A were observed in exposed patients with Luminal B subtype tumors, with high ki67 proliferation rates, high histological grade, and positive for the progesterone receptor. Reduced IL-4 was also seen in exposed women with lymph node invasion. Our data show that occupational exposure to pesticides induces significant changes in the levels of cytokines necessary for tumor control and correlates with poor prognosis clinical outcomes in breast cancer.

Brief research report pesticide occupational exposure leads to significant inflammatory changes in normal mammary breast tissue.

Studies have documented the high occurrence of several tumors, including female breast cancer, in populations occupationally exposed to pesticides worldwide. It is believed that in addition to direct DNA damage, other molecular alterations that indicate genomic instability are associated, such as epigenetic modifications and the production of inflammation mediators. The present study characterized the profile of inflammatory changes in the breast tissue of women without cancer occupationally exposed to pesticides. In samples of normal breast tissue collected during biopsy and evaluated as negative for cancer by a pathologist, oxidative stress levels were assessed as inflammatory markers through measurements of lipoperoxides and total antioxidant capacity of the sample (TRAP) by high-sensitivity chemiluminescence, as well as levels of nitric oxide (NOx) metabolites. The levels of inflammation-modulating transcription factors PPAR-γ (peroxisome proliferator-activated receptor gamma) and NF-κB (nuclear factor kappa B) were also quantified, in addition to the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin 12 (IL-12). The levels of lipoperoxides, TRAP, and NOx were significantly lower in the exposed group. On the other hand, PPAR-γ levels were increased in the breast tissue of exposed women, with no variation in NF-κB. There was also a rise of TNF-α in exposed women samples without significant variations in IL-12 levels. These findings suggest an inflammatory signature of the breast tissue associated with pesticide exposure, which may trigger mechanisms related to mutations and breast carcinogenesis.

Excess body weight significantly affects systemic and tumor inflammatory status and correlates to poor prognosis parameters in patients with breast cancer.

Introduction: Obesity is a pro-inflammatory disease critical for developing breast cancer (BC), which impacts the profiles of systemic inflammatory mediators and determinants of different disease clinical outcomes remains little explored. Methods: A total of 195 patients diagnosed with breast cancer were included. Aiming to exclude chemotherapy interference on circulating mediators, samples were collected at diagnosis, out of the treatment period. Patients were classified as normal weight (BMI up to 24.9 kg/m2) or overweight (BMI ≥25.0 kg/m2). Serum levels of IL-4, IL-12, hydroperoxides, and nitric oxide metabolites (NOx) were measured. Also, tumor expression of inducible nitric oxide synthase (iNOS), TGF-ß1, CD4+, and CD8+ lymphocytes were evaluated. Results: IL-4 levels were significantly increased in the overweight BC group (p = 0.0329), including patients with luminal B subtype (p = 0.0443), presence of lymph node metastases (p = 0.0115) and age of diagnosis below 50 years, (p = 0.0488). IL-12 levels were significantly increased in overweight BC patients with lymph node metastases (p = 0.0115). Hydroperoxides were increased in overweight BC patients (p = 0.0437), including those with tumors smaller than 2 cm (p = 0.05). NOx levels were also increased in overweight BC patients, including those with luminal B disorders (p = 0.0443), high-grade tumors (p = 0.0351) and lymph node metastases (p = 0.0155). The expression of iNOS (p < 0.001) and TCD4+ lymphocytes (p = 0.0378) was significantly investigated in tumor biopsies from overweight BC women. Conclusions: These data provide a picture of the influence of excess body weight on inflammatory mediators' systemic and tumoral profiles, especially in patients displaying poor outcome BC.

The Expression of CTLA-4 in Breast Tumors and Tumor-Infiltrating Leukocytes Affects Patients' Systemic Inflammatory Status and Varies According to Their Molecular Subtypes.

Recent evidence has pointed out that the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expression is a poor prognosis factor. However, the implications of CTLA-4 expression on circulating inflammatory mediators are unclear for breast cancer. Tumor biopsies and blood samples were collected from 117 breast cancer patients. Oxidative stress parameters were evaluated in plasma samples by measuring the lipoperoxidation profile and nitric oxide metabolites (NOx). Interleukins 12 (IL-12) and 4 (IL-4) were assessed by ELISA. CTLA-4 expression was determined by immunofluorescence assessed by its labeling in tumor-infiltrating leukocytes (TILs) or breast tumors. Correlations between CTLA-4 expression in breast tumors with TCD4/TCD8 infiltrating lymphocyte and inflammation-related genes were performed using data from TIMER 2.0/TCGA databases (n = 2160). CTLA-4 expression in TILs significantly correlated to triple-negative breast tumors. Patients carrying CTLA-4-positive tumors exhibited lower plasmatic NOx levels, and those expressing CTLA-4 in TILs had reduced levels of IL-12 in plasma. No changes in either IL-4 or lipid peroxidation profiles were detected concerning any CTLA4 status. Compared to the Luminal A ones, oxidative stress parameters and cytokines were observed in patients bearing triple-negative tumors. CTLA-4 expression in all breast cancer subtypes positively correlated to TCD4/TCD8 lymphocyte infiltrates, as well as to the pro-inflammatory genes IL12A, IL4, NFKB1, NFKB2, NOS1, NOS2, and NOS3. CTLA-4 expression in both tumor and TILs can affect the systemic inflammatory status of breast cancer patients, especially antitumor molecules such as IL-12 and NOx that correlate to more aggressive disease.

Naringenin and Hesperidin as Promising Alternatives for Prevention and Co-Adjuvant Therapy for Breast Cancer.

Citrus (genus Citrus L.) fruits are essential sources of bioactive compounds with antioxidant properties, such as flavonoids. These polyphenolic compounds are divided into subclasses, in which flavanones are the most prominent. Among them, naringenin and hesperidin are emerging compounds with anticancer potential, especially for breast cancer (BC). Several mechanisms have been proposed, including the modulation of epigenetics, estrogen signaling, induction of cell death via regulation of apoptotic signaling pathways, and inhibition of tumor invasion and metastasis. However, this information is sparse in the literature and needs to be brought together to provide an overview of how naringenin and hesperidin can serve as therapeutic tools for drug development and as a successful co-adjuvant strategy against BC. This review detailed such mechanisms in this context and highlighted how naringenin and hesperidin could interfere in BC carcinogenesis and be helpful as potential alternative therapeutic sources for breast cancer treatment.

Melatonin modulates the Warburg effect and alters the morphology of hepatocellular carcinoma cell line resulting in reduced viability and migratory potential.

AIMS: Hepatocellular Carcinoma (HCC) is a primary neoplasm derived from hepatocytes with low responsiveness and recurrent chemoresistance. Melatonin is an alternative agent that may be helpful in treating HCC. We aimed to study in HuH 7.5 cells whether melatonin treatment exerts antitumor effects and, if so, what cellular responses are induced and involved. MAIN METHODS: We evaluated the effects of melatonin on cell cytotoxicity and proliferation, colony formation, morphological and immunohistochemical aspects, and on glucose consumption and lactate release. KEY FINDINGS: Melatonin reduced cell motility and caused lamellar breakdown, membrane damage, and reduction in microvillus. Immunofluorescence analysis revealed that melatonin reduced TGF and N-cadherin expression, which was further associated with inhibition of epithelial-mesenchymal transition process. In relation to the Warburg-type metabolism, melatonin reduced glucose uptake and lactate production by modulating intracellular lactate dehydrogenase activity. SIGNIFICANCE: Our results indicate that melatonin can act upon pyruvate/lactate metabolism, preventing the Warburg effect, which may reflect in the cell architecture. We demonstrated the direct cytotoxic and antiproliferative effect of melatonin on the HuH 7.5 cell line, and suggest that melatonin is a promising candidate to be further tested as an adjuvant to antitumor drugs for HCC treatment.

Monitoring residues of pesticides in food in Brazil: A multiscale analysis of the main contaminants, dietary cancer risk estimative and mechanisms associated.

Introduction: Pesticides pose a risk for cancer development and progression. People are continuously exposed to such substances by several routes, including daily intake of contaminated food and water, especially in countries that are highly pesticide consumers and have very permissive legislation about pesticide contamination as Brazil. This work investigated the relationship among pesticides, food contamination, and dietary cancer risk. Methods: Analyzed two social reports from the Brazilian Government: the Program for Analysis of Residues of Pesticides in Food (PARA) and The National Program for Control of Waste and Contaminants (PNCRC). Results and discussion: First, we characterized the main pesticide residues detected over the maximum limits allowed by legislation or those prohibited for use in food samples analyzed across the country. Based on this list, we estimated the dietary cancer risks for some of the selected pesticides. Finally, we searched for data about dietary cancer risks and carcinogenic mechanisms of each pesticide. We also provided a critical analysis concerning the pesticide scenario in Brazil, aiming to discuss the food contamination levels observed from a geographical, political, and public health perspective. Exposures to pesticides in Brazil violate a range of human rights when food and water for human consumption are contaminated.

Acute effects of photobiomodulation applied on the dorsal root ganglion in gout model-induced rats.

Gouty arthritis is an inflammatory disease that triggers symptoms such as pain, swelling, and joint stiffness. Since its main therapy is medication, research on other forms of treatment that do not generate side effects is necessary. Given this, the objective of this research was to evaluate the effects of combined photobiomodulation (LASER and LED) applied on the dorsal root ganglion (DRG) in an experimental model of gouty arthritis. For this, 40 Wistar rats were randomized into 4 groups: simulation of the model with saline injection, without treatment (CTL; n = 10); gout simulation with photobiomodulation treatment (CTL-PBM; n = 10); gout model with the injection of monosodium urate crystals (1.25 mg) in the femorotibial joint, without treatment (GOT; n = 10); or gout model with photobiomodulation treatment (GOT-PBM; n = 10). After 7 h of gout induction, photobiomodulation was performed with a cluster of 4 diodes applied to the GRD region in animals from the CTL-PBM and GOT-PBM groups. After analysing the results, it was concluded that the therapy favored the reduction of edema and joint incapacity, as well as the increase in the nociceptive threshold and plantar grip strength. Furthermore, PBM stimulated an increase in the inflammatory response (with increased levels of IL-1ß and greater recruitment of leukocytes) and greater activation of the antioxidant system. Therefore, PBM can be considered an effective therapeutic alternative to improve the functional status in this model of joint disease.

Profiles of Expression of SAV1 in Normoxia or Hypoxia Microenviroment are Associated with Breast Cancer Prognosis.

BACKGROUND: In breast cancer (BC), hypoxia is associated with poor prognosis. Protein Salvador homolog 1 (SAV1) acts as a tumor suppressor and is downregulated in the cancer cells. However, there is limited data on the expression profile of SAV1 and its importance in BC. It has not been studied to evaluate this phenomenon in a hypoxic microenvironment yet. AIM: This study aimed to investigate SAV1 expression profiles under normoxia and hypoxia, and the potential of SAV1 in BC prognosis. METHODS: Gene and protein expression analyses were performed using Real-Time quantitative PCR (RT-qPCR) and immunocytochemistry (ICC), respectively, and in silico analyses were performed using The Cancer Genome Atlas (TCGA). The survival curves were constructed using KMplotter. RESULTS: SAV1 expression was lower in BC samples and tumor cell lines than in normal samples. The SAV1 mRNA levels were reduced in hypoxic estrogen receptor positive (ER+) tumors, which were associated with a lower survival probability as compared to normoxic ER+ tumors. Furthermore, lower levels of SAV1 were found in advanced cancer stage samples, which are associated with worse survival curves and can be a risk factor for BC. CONCLUSIONS: These data suggest a potential prognostic role of SAV1 in BC, with lower expressions associated with worse prognosis.

Occupational Exposure to Pesticides Affects Pivotal Immunologic Anti-Tumor Responses in Breast Cancer Women from the Intermediate Risk of Recurrence and Death.

Breast cancer risk stratification is a strategy based using on clinical parameters to predict patients' risk of recurrence or death, categorized as low, intermediate, or high risk. Both low and high risk are based on well-defined clinical parameters. However, the intermediate risk depends on more malleable parameters. It means an increased possibility for either suboptimal treatment, leading to disease recurrence, or systemic damage due to drug overload toxicity. Therefore, identifying new factors that help to characterize better the intermediate-risk stratification, such as environmental exposures, is necessary. For this purpose, we evaluated the impact of occupational exposure to pesticides on the systemic profile of cytokines (IL-12, IL-4, IL-17A, and TNF-α) and oxidative stress (hydroperoxides, total antioxidants, and nitric oxide metabolites), as well as TGF-ß1, CTLA-4, CD8, and CD4 expression, investigated in tumor cells. Occupational exposure to pesticides decreased the levels of IL-12 and significantly increased the expression of TGF-ß1 and CTLA-4 in the immune infiltrate. Nevertheless, we observed a decrease in CTLA-4 in tumor samples and CD8 in infiltrating cells of intermediate overweight or obese patients with at least one metastatic lymph node at the diagnosis. These findings indicate that occupational exposure to pesticides changes the molecular behavior of disease and should be considered for intermediate-risk stratification assessment in breast cancer patients.

Chemotherapy induces plasmatic antioxidant changes in pediatric patients with acute lymphoid leukemia B that correlate to disease prognosis.

Pediatric acute lymphoid leukemias (ALL) is the most common childhood cancer, and cytotoxic chemotherapy remains the primary treatment option. Chemotherapic drugs act by oxidative stress generation, but their clinical meaning is poorly understood. During the chemotherapy schedule, this study evaluated the antioxidant profile of peripheral blood samples from 34 patients diagnosed with type B-cell ALL (B-ALL). Peripheral blood samples were collected at diagnosis (D0) and during the induction, consolidation, and maintenance phases. The plasma total antioxidant capacity (TRAP) was determined using the high-sensitivity chemiluminescence technique. Antioxidant levels were higher on D0 compared to day 7 after treatment starting (D7) in the induction phase (28.68-1194.71 µM Trolox, p = 0.0178) and in the high-risk group (age > ten years and/or with white blood cell counts and/or > 50,000 white blood cells/m3 at diagnosis) concerning low-risk patients (253.79-1194.71 µM Trolox, p = 0.0314). Reduced TRAP was also detected in patients who died compared to those who survived (392.42-1194.71 µM Trolox, p = 0.0278). Patients under consolidation (56.14-352.05 µM Trolox, p=<0.0001) and maintenance (30.48-672.99 µM Trolox, p=<0.0001) showed a significant reduction in TRAP levels compared to those from the induction phase (28.68-1390.26 µM Trolox), reaching levels similar to cured patients out of treatment (64.82-437.82 µM Trolox). These findings suggest that the variation of the total antioxidant capacity in B-ALL during chemotherapy is a parameter that correlates to some predictors of disease prognosis.

Cross-sectional study for COVID-19-related mortality predictors in a Brazilian state-wide landscape: the role of demographic factors, symptoms and comorbidities.

OBJECTIVE: The Brazilian state of Paraná has suffered from COVID-19 effects, understanding predictors of increased mortality in health system interventions prevent hospitalisation of patients. We selected the best models to evaluate the association of death with demographic characteristics, symptoms and comorbidities based on three levels of clinical severity for COVID-19: non-hospitalised, hospitalised non-ICU ward and ICU ward. DESIGN: Cross-sectional survey using binomial mixed models. SETTING: COVID-19-positive cases diagnosed by reverse transcription-PCR of municipalities located in Paraná State. PATIENTS: Cases of anonymous datasets of electronic medical records from 1 April 2020 to 31 December 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: The best prediction factors were chosen based on criteria after a stepwise analysis using multicollinearity measure, lower Akaike information criterion and goodness-of-fit χ2 tests from univariate to multivariate contexts. RESULTS: Male sex was associated with increased mortality among non-hospitalised patients (OR 1.76, 95% CI 1.47 to 2.11) and non-ICU patients (OR 1.22, 95% CI 1.05 to 1.43) for symptoms and for comorbidities (OR 1.89, 95% CI 1.59 to 2.25, and OR 1.30, 95% CI 1.11 to 1.52, respectively). Higher mortality occurred in patients older than 35 years in non-hospitalised (for symptoms: OR 4.05, 95% CI 1.55 to 10.54; and for comorbidities: OR 3.00, 95% CI 1.24 to 7.27) and in hospitalised over 40 years (for symptoms: OR 2.72, 95% CI 1.08 to 6.87; and for comorbidities: OR 2.66, 95% CI 1.22 to 5.79). Dyspnoea was associated with increased mortality in non-hospitalised (OR 4.14, 95% CI 3.45 to 4.96), non-ICU (OR 2.41, 95% CI 2.04 to 2.84) and ICU (OR 1.38, 95% CI 1.10 to 1.72) patients. Neurological disorders (OR 2.16, 95% CI 1.35 to 3.46), neoplastic (OR 3.22, 95% CI 1.75 to 5.93) and kidney diseases (OR 2.13, 95% CI 1.36 to 3.35) showed the majority of increased mortality for ICU as well in the three levels of severity jointly with heart disease, diabetes and CPOD. CONCLUSIONS: These findings highlight the importance of the predictor's assessment for the implementation of public healthcare policy in response to the COVID-19 pandemic, mainly to understand how non-pharmaceutical measures could mitigate the virus impact over the population.

Corrigendum: Somatic DNA damage response and homologous repair gene alterations and its association with tumor variant burden in breast cancer patients with occupational exposure to pesticides.

[This corrects the article DOI: 10.3389/fonc.2022.904813.].

Grandiflorenic acid from Wedelia trilobata plant induces apoptosis and autophagy cell death in breast adenocarcinoma (MCF7), lung carcinoma (A549), and hepatocellular carcinoma (HuH7.5) cells lines.

INTRODUCTION: Wedelia trilobata (Sphagneticola trilobata) is a plant used in this popular medicine for treating infectious, sores and swellings in some rural communities, and their extract has antioxidant, anti-inflammatory, antitumor and hepatoprotective effect. Cancer is a molecularly heterogeneous disease caused by environmental and, genetic factors, among others. Since the complexity of the disease leads to low response rates to the different treatments used, it is necessary to find alternative drugs aimed at its control. The objective of our study was to assess whether grandiflorenic acid (GFA) has antitumor activity on breast (MCF7), liver (HuH7.5), and lung (A549) tumor cell lines. METHODS: We used cell integrity assessment methods to assess whether (GFA) would be cytotoxic for tumor cell lines at doses ranging from and the pattern of death involved in this effect. RESULTS: Treatment using GFA significantly inhibited cell proliferation in the three studied cells, followed by a decrease in cell size. The assessment of the death mechanisms showed the treatments increased the production of reactive oxygen species, caused exposure of phosphatidylserine, depolarization of the mitochondrial membrane, and, decrease plasma membrane integrity, indicating mechanisms related to apoptosis. Besides, we found the formation of autophagy vacuoles in our tests. CONCLUSION: Finally, our study found the effect of GFA on breast (MCF7), lung (A549), and liver (HuH7.5) tumor cell lines induce cytotoxicity and patterns of death associated with apoptosis and autophagy, and oxidative stress generation plays a role in these two pathways of cell death. Thus, this study revealed GFA exhibits anti-cancer activity in vitro and could help future studies to improve strategies for cancer treatment with involving natural compounds.

An Overview Regarding Pharmacogenomics and Biomarkers Discovery: Focus on Breast Cancer.

Breast cancer represents a health concern worldwide for being the leading cause of cancer- related women's death. The main challenge for breast cancer treatment involves its heterogeneous nature with distinct clinical outcomes. It is clinically categorized into five subtypes: luminal A; luminal B, HER2-positive, luminal-HER, and triple-negative. Despite the significant advances in the past decades, critical issues involving the development of efficient target-specific therapies and overcoming treatment resistance still need to be better addressed. OMICs-based strategies have marked a revolution in cancer biology comprehension in the past two decades. It is a consensus that Next-Generation Sequencing (NGS) is the primary source of this revolution and the development of relevant consortia translating pharmacogenomics into clinical practice. Still, new approaches, such as CRISPR editing and epigenomic sequencing are essential for target and biomarker discoveries. Here, we discuss genomics and epigenomics techniques, how they have been applied in clinical management and to improve therapeutic strategies in breast cancer, as well as the pharmacogenomics translation into the current and upcoming clinical routine.

Somatic DNA Damage Response and Homologous Repair Gene Alterations and Its Association With Tumor Variant Burden in Breast Cancer Patients With Occupational Exposure to Pesticides.

Homologous recombination is a crucial pathway that is specialized in repairing double-strand breaks; thus, alterations in genes of this pathway may lead to loss of genomic stability and cell growth suppression. Pesticide exposure potentially increases cancer risk through several mechanisms, such as the genotoxicity caused by chronic exposure, leading to gene alteration. To analyze this hypothesis, we investigated if breast cancer patients exposed to pesticides present a different mutational pattern in genes related to homologous recombination (BRCA1, BRCA2, PALB2, and RAD51D) and damage-response (TP53) concerning unexposed patients. We performed multiplex PCR-based assays and next-generation sequencing (NGS) of all coding regions and flanking splicing sites of BRCA1, BRCA2, PALB2, TP53, and RAD51D in 158 unpaired tumor samples from breast cancer patients on MiSeq (Illumina) platform. We found that exposed patients had tumors with more pathogenic and likely pathogenic variants than unexposed patients (p = 0.017). In general, tumors that harbored a pathogenic or likely pathogenic variant had a higher mutational burden (p < 0.001). We also observed that breast cancer patients exposed to pesticides had a higher mutational burden when diagnosed before 50 years old (p = 0.00978) and/or when carrying BRCA1 (p = 0.0138), BRCA2 (p = 0.0366), and/or PALB2 (p = 0.00058) variants, a result not found in the unexposed group. Our results show that pesticide exposure impacts the tumor mutational landscape and could be associated with the carcinogenesis process, therapy response, and disease progression. Further studies should increase the observation period in exposed patients to better evaluate the impact of these findings.