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1.
Environ Sci Process Impacts ; 22(3): 824-832, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32159184

RESUMO

In exploration of congenital heart defects produced by TCE, Hepatocyte Nuclear Factor 4 alpha (HNF4a) transcriptional activity was identified as a central component. TCE exposure altered gene transcription in the chick heart in a non-monotonic pattern where only low dose exposure inhibited transcription by HNF4a. As the chick embryo is non-placental, we examine here HNF4a as a target of TCE in developing mouse embryos. Benfluorex and Bi6015, published agonist and antagonist, respectively, of HNF4a were compared to low dose TCE exposure. Pregnant mice were exposed to 10 ppb (76 nM) TCE, 5 µM Benfluorex, 5 µM Bi6015, or a combination of Bi6015 and TCE in drinking water. Litters (E12) were collected during a sensitive window in heart development. Embryonic hearts were collected, pooled for extraction of RNA and marker expression was examined by quantitative PCR. Multiple markers, previously identified as sensitive to TCE exposure in chicks or as published targets of HNF4a transcription were significantly affected by Benfluorex, Bi6015 and TCE. Activity of TCE and both HNF4a-specific reagents on transcription argues that HNF4a is a component of TCE cardiotoxicity and likely a proximal target of low dose exposure during development. The effectiveness of these reagents after delivery in maternal drinking water suggests that neither maternal metabolism, nor placental transport is protective of exposure.

2.
Br J Pharmacol ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31691272

RESUMO

Breast cancer (BC) is the most common cancer and second leading cause of cancer mortality in women worldwide. Validated biomarkers enhance efforts for early detection and treatment, which reduce the risk of mortality. Epigenetic signatures have been suggested as good biomarkers for early detection, prognosis and targeted therapy of BC. Here, we highlight studies documenting the modifying effects of dietary fatty acids and obesity on BC biomarkers associated with DNA methylation. We focus our analysis on changes elicited in writers of DNA methylation (i.e., DNA methyltransferases), global DNA methylation and gene-specific DNA methylation. To provide context, we precede this discussion with a review of the available evidence for an association between BC incidence and both dietary fat consumption and obesity. We also include a review of well-vetted BC biomarkers related to cytosine-guanine dinucleotides methylation and how they influence BC risk, prognosis, tumour characteristics and response to treatment.

3.
Nutrients ; 11(11)2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31652854

RESUMO

Triple negative breast cancers (TNBC) are the most aggressive and lethal breast cancers (BC). The aryl hydrocarbon receptor (AHR) is often overexpressed in TNBC, and its activation results in the epigenetic silencing of BRCA1, which is a necessary factor for the transcriptional activation of estrogen receptor (ER)α. The dietary isoflavone genistein (GEN) modulates BRCA1 CpG methylation in BC cells. The purpose of this study was to investigate the effect of GEN on BRCA1 epigenetic regulation and AHR activity in vivo and TNBC cells. Mice were administered a control or GEN-enriched (4 and 10 ppm) diet from gestation through post-natal day 50. Mammary tissue was analyzed for changes in BRCA1 regulation and AhR activity. TNBC cells with constitutively hypermethylated BRCA1 (HCC38) and MCF7 cells were used. Protein levels and mRNA expression were measured by Western blot and real-time PCR, respectively. BRCA1 promoter occupancy and CpG methylation were analyzed by chromatin immunoprecipitation and methylation-specific PCR, respectively. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. GEN administered in the diet dose-dependently decreased basal Brca1 methylation and AHR activity in the mammary gland of adult mice. HCC38 cells were found to overexpress constitutively active AHR in parallel with BRCA1 hypermethylation. The treatment of HCC38 cells with GEN upregulated BRCA1 protein levels, which was attributable to decreased CpG methylation and AHR binding at BRCA1 exon 1a. In MCF7 cells, GEN prevented the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-dependent localization of AHR at the BRCA1 gene. These effects were consistent with those elicited by control AHR antagonists galangin (GAL), CH-223191, and α-naphthoflavone. The pre-treatment with GEN sensitized HCC38 cells to the antiproliferative effects of 4-hydroxytamoxifen. We conclude that the dietary compound GEN may be effective for the prevention and reversal of AHR-dependent BRCA1 hypermethylation, and the restoration of ERα-mediated response, thus imparting the sensitivity of TNBC to antiestrogen therapy.

5.
Nutrients ; 11(1)2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30650553

RESUMO

The farnesoid-X-receptor (FXR) protects against inflammation and cancer of the colon through maintenance of intestinal bile acid (BA) homeostasis. Conversely, higher levels of BA and cyclooxygenase-2 (COX-2) are risk factors for inflammation and cancer of the colon. In the United States, n-6 linoleic acid (LA) is the most commonly used dietary vegetable fat. Metabolism of n-6 fatty acids has been linked to a higher risk of intestinal cancer. The objectives of this study were to investigate in colonic mucosa the effects of a high-fat diet rich in LA (n-6HFD) on CpG methylation of Fxr and prostaglandin-endoperoxide synthase-2 (Ptsg-2) genes, and the impact on the expression of tumor suppressor adenomatous polyposis Coli (Apc) and proliferative cyclin D1 (Ccnd1) genes. Weaned C57BL/6J male mice were fed for 6 weeks either an n-6HFD containing 44% energy (44%E) from 22% safflower oil (SO, 76% LA by weight) or a 13% energy (13%E) control diet (Control) from SO (5% by weight). Mice fed the n-6HFD had reduced (60%) Fxr promoter CpG methylation and increased (~50%) Fxr mRNA. The expression of FXR-target ileal bile acid-binding protein (Ibabp), small heterodimer protein (Shp), and anti-inflammatory peroxisome proliferator-activated-γ1 genes was increased. The n-6HFD reduced Ptgs-2 CpG methylation, increased the expression of Cox-2, and increased Apc CpG methylation in colonic mucosa. Accordingly, reduced expression of Apc was coupled to accumulation of c-JUN and Ccnd1, respectively cofactor and gene targets for the ß-catenin/Wnt signaling pathway. Finally, the n-6HFD reduced the expression of histone deacetylase-1 while favoring the accumulation of acetylated histone 3. We conclude that an n-6HFD epigenetically modifies Fxr, leading to the activation of downstream factors that participate in BA homeostasis. However, epigenetic activation of Ptsg-2 coupled with silencing of Apc and accumulation of C-JUN and Ccnd1 may increase the risk of inflammation and cancer of the colon.


Assuntos
Colo/efeitos dos fármacos , Neoplasias do Colo/etiologia , Metilação de DNA/efeitos dos fármacos , Epigênese Genética , Inflamação/etiologia , Mucosa Intestinal/efeitos dos fármacos , Ácido Linoleico/efeitos adversos , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Células Cultivadas , Colite/etiologia , Colite/genética , Colite/metabolismo , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/efeitos adversos , Pesquisa Fetal , Genes jun , Humanos , Inflamação/genética , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Ácido Linoleico/farmacologia , Camundongos Endogâmicos C57BL , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
6.
Int J Oncol ; 54(3): 869-878, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30664189

RESUMO

A significant percentage (~30%) of estrogen receptor­α (ERα)­positive tumors become refractory to endocrine therapies; however, the mechanisms responsible for this resistance remain largely unknown. Chronic exposure to arsenic through foods and contaminated water has been linked to an increased incidence of several tumors and long­term health complications. Preclinical and population studies have indicated that arsenic exposure may interfere with endocrine regulation and increase the risk of breast tumorigenesis. In this study, we examined the effects of sodium arsenite (NaAsIII) exposure in ERα­positive breast cancer cells in vitro and in mammary tumor xenografts. The results revealed that acute (within 4 days) and long­term (10 days to 7 weeks) in vitro exposure to environmentally relevant doses reduced breast cancer 1 (BRCA1) and ERα expression associated with the gain of cyclin D1 (CCND1) and folate receptor 1 (FOLR1), and the loss of methylenetetrahydrofolate reductase (MTHFR) expression. Furthermore, long­term exposure to NaAsIII induced the proliferation and compromised the response of MCF7 cells to tamoxifen (TAM). The in vitro exposure to NaAsIII induced BRCA1 CpG methylation associated with the increased recruitment of DNA methyltransferase 1 (DNMT1) and the loss of RNA polymerase II (PolII) at the BRCA1 gene. Xenografts of NaAsIII­preconditioned MCF7 cells (MCF7NaAsIII) into the mammary fat pads of nude mice produced a larger tumor volume compared to tumors from control MCF7 cells and were more refractory to TAM in association with the reduced expression of BRCA1 and ERα, CpG hypermethylation of estrogen receptor 1 (ESR1) and BRCA1, and the increased expression of FOLR1. These cumulative data support the hypothesis that exposure to AsIII may contribute to reducing the efficacy of endocrine therapy against ERα­positive breast tumors by hampering the expression of ERα and BRCA1 via CpG methylation, respectively of ESR1 and BRCA1.


Assuntos
Antineoplásicos Hormonais/farmacologia , Arsenitos/toxicidade , Proteína BRCA1/genética , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Compostos de Sódio/toxicidade , Tamoxifeno/farmacologia , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Metilação de DNA/efeitos dos fármacos , Exposição Ambiental , Epigênese Genética/efeitos dos fármacos , Feminino , Receptor 1 de Folato/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Regiões Promotoras Genéticas/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Yale J Biol Med ; 91(2): 105-127, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29962921

RESUMO

Breast cancer is the most common type of cancer and leading cause of cancer mortality among women worldwide. However, the majority of breast malignancies are of sporadic etiology. Therefore, identifying risk-mitigating factors may significantly decrease the burden of breast cancer. Diet can have both a predisposing and protective role in breast tumorigenesis. However, establishing efficacy of dietary constituents for cancer prevention has been limited by suboptimal dietary assessment. There is a need to acquire new experimental evidence that can be used to discriminate beneficial from harmful dietary constituents. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is recognized as the mediator of halogenated and polycyclic aromatic hydrocarbon toxicities. Importantly, evidence points to a breast tumor-promoting role for the AhR. Preclinical and clinical studies suggest that the AhR is overexpressed in advanced and triple negative breast cancers. Several dietary constituents, namely flavonoid compounds, have demonstrated inhibitory effects on AhR activation. Given this background, in this paper we elaborate on the working hypothesis that a diet rich in AhR food agonists favors breast tumor development, whereas a diet rich in AhR food antagonists is protective. As an initial approach to developing an AhR diet hypothesis, we conducted a review of published studies reporting on the association between intake of AhR inhibitory foods and risk of breast cancer. To assist the reader with interpretation of the concepts leading to the AhR diet hypothesis, we have preceded this review with an overview of AhR biology and its role in breast cancer development.


Assuntos
Neoplasias da Mama/metabolismo , Dieta , Receptores de Hidrocarboneto Arílico/metabolismo , Neoplasias da Mama/genética , Epigenômica , Feminino , Flavonoides/metabolismo , Humanos , Receptores de Hidrocarboneto Arílico/genética
8.
Toxicol Lett ; 285: 113-120, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29306027

RESUMO

Exposure to trichloroethylene (TCE) is linked to formation of congenital heart defects in humans and animals. Prior interactome analysis identified the transcription factor, Hepatocyte Nuclear Factor 4 alpha (HNF4a), as a potential target of TCE exposure. As a role for HNF4a is unknown in the heart, we examined developing avian hearts for HNF4a expression and for sensitivity to TCE and the HNF4a agonist, Benfluorex. In vitro analysis using a HNF4a reporter construct showed both TCE and HFN4a to be antagonists of HNF4a-mediated transcription at the concentrations tested. HNF4a mRNA is expressed transiently in the embryonic heart during valve formation and cardiac development. Embryos were examined for altered gene expression in the presence of TCE or Benfluorex. TCE altered expression of selected mRNAs including HNF4a, TRAF6 and CYP2C45. There was a transition between inhibition and induction of marker gene expression in embryos as TCE concentration increased. Benfluorex was largely inhibitory to selected markers. Echocardiography of exposed embryos showed reduced cardiac function with both TCE and Benfluorex. Cardiac contraction was reduced by 29% and 23%, respectively at 10 ppb. The effects of TCE and Benfluorex on autocrine regulation of HNF4a, selected markers and cardiac function argue for a functional interaction of TCE and HNF4a. Further, the dose-sensitive shift between inhibition and induction of marker expression may explain the nonmonotonic-like dose response observed with TCE exposure in the heart.


Assuntos
Poluentes Ambientais/toxicidade , Coração/efeitos dos fármacos , Fator 4 Nuclear de Hepatócito/genética , Transcrição Genética/efeitos dos fármacos , Tricloroetileno/toxicidade , Animais , Embrião de Galinha , Relação Dose-Resposta a Droga , Ecocardiografia , Fenfluramina/análogos & derivados , Fenfluramina/farmacologia , Genes Reporter , Coração/diagnóstico por imagem , Coração/embriologia , Células Hep G2 , Fator 4 Nuclear de Hepatócito/agonistas , Humanos , Miocárdio/metabolismo
9.
Front Nutr ; 4: 59, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29259973

RESUMO

Colorectal cancer (CRC) is the third most common cancer diagnosis and the second and third leading cause of cancer mortality in men and women, respectively. However, the majority of CRC cases are the result of sporadic tumorigenesis via the adenoma-carcinoma sequence. This process can take up to 20 years, suggesting an important window of opportunity exists for prevention such as switching toward healthier dietary patterns. The Mediterranean diet (MD) is a dietary pattern associated with various health benefits including protection against cardiovascular disease, diabetes, obesity, and various cancers. In this article, we review publications available in the PubMed database within the last 10 years that report on the impact of a MD eating pattern on prevention of CRC. To assist the reader with interpretation of the results and discussion, we first introduce indexes and scoring systems commonly used to experimentally determine adherence to a MD, followed by a brief introduction of the influence of the MD pattern on inflammatory bowel disease, which predisposes to CRC. Finally, we discuss key biological mechanisms through which specific bioactive food components commonly present in the MD are proposed to prevent or delay the development of CRC. We close with a discussion of future research frontiers in CRC prevention with particular reference to the role of epigenetic mechanisms and microbiome related to the MD eating pattern.

10.
Nutr Today ; 52(5): 208-222, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29051674

RESUMO

A large body of research data suggests that traditional dietary habits and lifestyle unique to the Mediterranean region (Mediterranean diet, MD) lower the incidence of chronic diseases and improve longevity. These data contrast with troubling statistics in the United States and other high income countries pointing to an increase in the incidence of chronic diseases and the projected explosion in cost of medical care associated with an aging population. In 2013, the MD was inscribed by UNESCO in the "Representative List of the Intangible Cultural Heritage of Humanity." The 2015-2020 Dietary Guidelines for Americans included the MD as a healthy dietary pattern. Therefore, specific objectives of this article are to provide an overview of the nutritional basis of this healthful diet, its metabolic benefits, and its role in multiple aspects of disease prevention and healthy aging. Whereas recommendations about the MD often focus on specific foods or bioactive compounds, we suggest that the eating pattern as a whole likely contributes to the health promoting effects of the MD.

11.
Curr Dev Nutr ; 1(6): e000562, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29955703

RESUMO

Background: Previous studies have suggested a causative role for agonists of the aromatic hydrocarbon receptor (AhR) in the etiology of breast cancer 1, early-onset (BRCA-1)-silenced breast tumors, for which prospects for treatment remain poor. Objectives: We investigated the regulation of BRCA1 by the soy isoflavone genistein (GEN) in human estrogen receptor α (ERα)-positive Michigan Cancer Foundation-7 (MCF-7) and ERα-negative sporadic University of Arizona Cell Culture-3199 (UACC-3199) breast cancer cells, respectively, with inducible and constitutively active AhR. Methods: In MCF-7 cells, we analyzed the dose- and time-dependent effects of GEN and (-)-epigallocatechin-3-gallate (EGCG) control, selected as prototype dietary DNA methyltransferase (DNMT) inhibitors, on BRCA-1 expression after AhR activation with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in TCDD-washout experiments. We compared the effects of GEN and EGCG on BRCA1 cytosine-phosphate-guanine (CpG) methylation and cell proliferation. Controls for DNA methylation and proliferation were changes in expression of DNMT-1, cyclin D1, and p53, respectively. In UACC-3199 cells, we compared the effects of GEN and α-naphthoflavone (αNF; 7,8-benzoflavone), a synthetic flavone and AhR antagonist, on BRCA1 expression and CpG methylation, cyclin D1, and cell growth. Finally, we examined the effects of GEN and αNF on BRCA1, AhR-inducible cytochrome P450 (CYP)-1A1 (CYP1A1) and CYP1B1, and AhR mRNA expression. Results: In MCF-7 cells, GEN exerted dose- and time-dependent preventative effects against TCDD-dependent downregulation of BRCA-1. After TCDD washout, GEN rescued BRCA-1 protein expression while reducing DNMT-1 and cyclin D1. GEN and EGCG reduced BRCA1 CpG methylation and cell proliferation associated with increased p53. In UACC-3199 cells, GEN reduced BRCA1 and estrogen receptor-1 (ESR1) CpG methylation, cyclin D1, and cell growth while inducing BRCA-1 and CYP1A1. Conclusions: Results suggest preventative effects for GEN and EGCG against BRCA1 CpG methylation and downregulation in ERα-positive breast cancer cells with activated AhR. GEN and flavone antagonists of AhR may be useful for reactivation of BRCA1 and ERα via CpG demethylation in ERα-negative breast cancer cells harboring constitutively active AhR.

12.
Mol Nutr Food Res ; 60(6): 1310-29, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27144894

RESUMO

SCOPE: Reduced expression of tumor suppressor genes (TSG) increases the susceptibility to breast cancer. However, only a small percentage of breast tumors is related to family history and mutational inactivation of TSG. Epigenetics refers to non-mutational events that alter gene expression. Endocrine disruptors found in foods and drinking water may disrupt epigenetically hormonal regulation and increase breast cancer risk. This review centers on the working hypothesis that agonists of the aromatic hydrocarbon receptor (AHR), bisphenol A (BPA), and arsenic compounds, induce in TSG epigenetic signatures that mirror those often seen in sporadic breast tumors. Conversely, it is hypothesized that bioactive food components that target epigenetic mechanisms protect against sporadic breast cancer induced by these disruptors. METHODS AND RESULTS: This review highlights (i) overlaps between epigenetic signatures placed in TSG by AHR-ligands, BPA, and arsenic with epigenetic alterations associated with sporadic breast tumorigenesis; and (ii) potential opportunities for the prevention of sporadic breast cancer with food components that target the epigenetic machinery. CONCLUSIONS: Characterizing the overlap between epigenetic signatures elicited in TSG by endocrine disruptors with those observed in sporadic breast tumors may afford new strategies for breast cancer prevention with specific bioactive food components or diet.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Dieta , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Animais , Arsênico/análise , Arsênico/toxicidade , Compostos Benzidrílicos/análise , Compostos Benzidrílicos/toxicidade , Modelos Animais de Doenças , Disruptores Endócrinos/toxicidade , Feminino , Ácido Fólico/administração & dosagem , Ácido Fólico/análise , Análise de Alimentos , Contaminação de Alimentos/análise , Genes Supressores de Tumor/efeitos dos fármacos , Genisteína/administração & dosagem , Genisteína/análise , Humanos , Isotiocianatos/administração & dosagem , Isotiocianatos/análise , Fenóis/análise , Fenóis/toxicidade , Compostos Fitoquímicos/administração & dosagem , Compostos Fitoquímicos/análise , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Vitamina B 12/administração & dosagem , Vitamina B 12/análise
13.
J Nutr ; 146(2): 236-42, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26609171

RESUMO

BACKGROUND: The farnesoid X receptor (FXR) regulates bile acid (BA) metabolism and possesses tumor suppressor functions. FXR expression is reduced in colorectal tumors of subjects carrying inactivated adenomatous polyposis coli (APC). Identifying the mechanisms responsible for this reduction may offer new molecular targets for colon cancer prevention. OBJECTIVE: We investigated how APC inactivation influences the regulation of FXR expression in colonic mucosal cells. We hypothesized that APC inactivation would epigenetically repress nuclear receptor subfamily 1, group H, member 4 (FXR gene name) expression through increased CpG methylation. METHODS: Normal proximal colonic mucosa and normal-appearing adjacent colonic mucosa and colon tumors were collected from wild-type C57BL/6J and Apc-deficient (Apc(Min) (/+)) male mice, respectively. The expression of Fxr, ileal bile acid-binding protein (Ibabp), small heterodimer partner (Shp), and cyclooxygenase-2 (Cox-2) were determined by real-time polymerase chain reaction. In both normal and adjacent colonic mucosa and colon tumors, we measured CpG methylation of Fxr in bisulfonated genomic DNA. In vitro, we measured the impact of APC inactivation and deoxycholic acid (DCA) treatment on FXR expression in human colon cancer HCT-116 cells transfected with silencing RNA for APC and HT-29 cells carrying inactivated APC. RESULTS: In Apc(Min) (/+) mice, constitutive CpG methylation of the Fxrα3/4 promoter was linked to reduced (60-90%) baseline Fxr, Ibabp, and Shp and increased Cox-2 expression in apparently normal adjacent mucosa and colon tumors. Apc knockdown in HCT-116 cells increased cellular myelocytomatosis (c-MYC) and lowered (∼50%) FXR expression, which was further reduced (∼80%) by DCA. In human HCT-116 but not HT-29 colon cancer cells, DCA induced FXR expression and lowered CpG methylation of FXR. CONCLUSIONS: We conclude that the loss of APC function favors the silencing of FXR expression through CpG hypermethylation in mouse colonic mucosa and human colon cells, leading to reduced expression of downstream targets (SHP, IBABP) involved in BA homeostasis while increasing the expression of factors (COX-2, c-MYC) that contribute to inflammation and colon cancer.


Assuntos
Polipose Adenomatosa do Colo/genética , Ácidos e Sais Biliares/metabolismo , Neoplasias do Colo/genética , Metilação de DNA , Inativação Gênica , Genes APC , Receptores Citoplasmáticos e Nucleares/genética , Adenocarcinoma/genética , Animais , Colo/metabolismo , Ciclo-Oxigenase 2/metabolismo , Expressão Gênica , Células HCT116 , Células HT29 , Humanos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo
14.
BMC Cancer ; 15: 1026, 2015 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-26715507

RESUMO

BACKGROUND: Only 5-10% of breast cancer cases is linked to germline mutations in the BRCA-1 gene and occurs early in life. Conversely, sporadic breast tumors, which represent 90-95% of breast malignancies, have lower BRCA-1 expression, but not mutated BRCA-1 gene, and tend to occur later in life in combination with other genetic alterations and/or environmental exposures. The latter may include environmental and dietary factors that activate the aromatic hydrocarbon receptor (AhR). Therefore, understanding if changes in expression and/or activation of the AhR are associated with somatic inactivation of the BRCA-1 gene may provide clues for breast cancer therapy. METHODS: We evaluated Brca-1 CpG promoter methylation and expression in mammary tumors induced in Sprague-Dawley rats with the AhR agonist and mammary carcinogen 7,12-dimethyl-benzo(a)anthracene (DMBA). Also, we tested in human estrogen receptor (ER)α-negative sporadic UACC-3199 and ERα-positive MCF-7 breast cancer cells carrying respectively, hyper- and hypomethylated BRCA-1 gene, if the treatment with the AhR antagonist α-naphthoflavone (αNF) modulated BRCA-1 and ERα expression. Finally, we examined the association between expression of AhR and BRCA-1 promoter CpG methylation in human triple-negative (TNBC), luminal-A (LUM-A), LUM-B, and epidermal growth factor receptor-2 (HER-2)-positive breast tumor samples. RESULTS: Mammary tumors induced with DMBA had reduced BRCA-1 and ERα expression; higher Brca-1 promoter CpG methylation; increased expression of Ahr and its downstream target Cyp1b1; and higher proliferation markers Ccnd1 (cyclin D1) and Cdk4. In human UACC-3199 cells, low BRCA-1 was paralleled by constitutive high AhR expression; the treatment with αNF rescued BRCA-1 and ERα, while enhancing preferential expression of CYP1A1 compared to CYP1B1. Conversely, in MCF-7 cells, αNF antagonized estradiol-dependent activation of BRCA-1 without effects on expression of ERα. TNBC exhibited increased basal AhR and BRCA-1 promoter CpG methylation compared to LUM-A, LUM-B, and HER-2-positive breast tumors. CONCLUSIONS: Constitutive AhR expression coupled to BRCA-1 promoter CpG hypermethylation may be predictive markers of ERα-negative breast tumor development. Regimens based on selected AhR modulators (SAhRMs) may be useful for therapy against ERα-negative tumors, and possibly, TNBC with increased AhR and hypermethylated BRCA-1 gene.


Assuntos
Proteína BRCA1/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias da Mama/genética , Metilação de DNA , Receptor alfa de Estrogênio/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Biomarcadores Tumorais/genética , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Ilhas de CpG , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-Dawley
15.
Anticancer Agents Med Chem ; 15(1): 4-14, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25329591

RESUMO

The Breast Cancer 1 protein (BRCA1) is a tumor suppressor involved in basic cellular functions necessary for cell replication and DNA synthesis, but reduced expression of BRCA1, due to mutations or epigenetic inactivation, leads to impaired mammary gland differentiation and increased risk of breast cancer development. Although BRCA1 acts as a tumor suppressor and is present in all cells, where it is essential for the maintenance of the genome integrity, it is still not clear why mutations in the BRCA1 gene predispose to breast and ovarian, but not to other types of cancer. In the first part of this review, we briefly discuss the function and regulation of the BRCA1 protein, including its role associated with familial and sporadic breast cancer. The second part is an overview of the therapeutic compounds used for breast cancer treatment targeting BRCA1, and the natural food components that hold potential preventive effect against those types of breast cancer in which BRCA1 expression is either reduced or lacking. Further studies elucidating the interactions between dietary compounds and cellular pathways, involved in regulation of BRCA1expression, are necessary for the development of strategies that may successfully prevent or treat breast cancer.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteína BRCA1/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Genes BRCA1/efeitos dos fármacos , Animais , Feminino , Genes Supressores de Tumor/efeitos dos fármacos , Humanos
16.
Mol Carcinog ; 54(4): 261-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24136580

RESUMO

Studies with murine models suggest that maternal exposure to aromatic hydrocarbon receptor (AhR) agonists may impair mammary gland differentiation and increase the susceptibility to mammary carcinogenesis in offspring. However, the molecular mechanisms responsible for these perturbations remain largely unknown. Previously, we reported that the AhR agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced CpG methylation of the breast cancer-1 (BRCA-1) gene and reduced BRCA-1 expression in breast cancer cell lines. Based on the information both the human and rat BRCA-1 genes harbor xenobiotic responsive elements (XRE = 5'-GCGTG-3'), which are binding targets for the AhR, we extended our studies to the analysis of offspring of pregnant Sprague-Dawley rats treated during gestation with TCDD alone or in combination with the dietary AhR antagonist resveratrol (Res). We report that the in utero exposure to TCDD increased the number of terminal end buds (TEB) and reduced BRCA-1 expression in mammary tissue of offspring. The treatment with TCDD induced occupancy of the BRCA-1 promoter by DNA methyltransferase-1 (DNMT-1), CpG methylation of the BRCA-1 promoter, and expression of cyclin D1 and cyclin-dependent kinase-4 (CDK4). These changes were partially overridden by pre-exposure to Res, which stimulated the expression of the AhR repressor (AhRR) and its recruitment to the BRCA-1 gene. These findings point to maternal exposure to AhR agonists as a risk factor for breast cancer in offspring through epigenetic inhibition of BRCA-1 expression, whereas dietary antagonists of the AhR may exert protective effects.


Assuntos
Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/prevenção & controle , Genes BRCA1/efeitos dos fármacos , Exposição Materna/efeitos adversos , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/agonistas , Estilbenos/uso terapêutico , Teratogênios/toxicidade , Animais , Anticarcinógenos/uso terapêutico , Proteína BRCA1/genética , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/patologia , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Gravidez , Regiões Promotoras Genéticas/efeitos dos fármacos , Ratos Sprague-Dawley , Resveratrol
17.
Adv Nutr ; 5(4): 373-85, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25022987

RESUMO

Posttranslational modifications of histones, alterations in the recruitment and functions of non-histone proteins, DNA methylation, and changes in expression of noncoding RNAs contribute to current models of epigenetic regulation. Nuclear receptors (NRs) are a group of transcription factors that, through ligand-binding, act as sensors to changes in nutritional, environmental, developmental, pathophysiologic, and endocrine conditions and drive adaptive responses via gene regulation. One mechanism through which NRs direct gene expression is the assembly of transcription complexes with cofactors and coregulators that possess chromatin-modifying properties. Chromatin modifications can be transient or become part of the cellular "memory" and contribute to genomic imprinting. Because many food components bind to NRs, they can ultimately influence transcription of genes associated with biologic processes, such as inflammation, proliferation, apoptosis, and hormonal response, and alter the susceptibility to chronic diseases (e.g., cancer, diabetes, obesity). The objective of this review is to highlight how NRs influence epigenetic regulation and the relevance of dietary compound-NR interactions in human nutrition and for disease prevention and treatment. Identifying gene targets of unliganded and bound NRs may assist in the development of epigenetic maps for food components and dietary patterns. Progress in these areas may lead to the formulation of disease-prevention models based on epigenetic control by individual or associations of food ligands of NRs.


Assuntos
Doença Crônica/prevenção & controle , Metilação de DNA , Dieta , Epigênese Genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Humanos
18.
Cardiovasc Toxicol ; 13(1): 77-84, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22855351

RESUMO

Trichloroethylene (TCE) is an organic solvent and common environmental contaminant. TCE exposure is associated with heart defects in humans and animal models. Primary metabolism of TCE in adult rodent models is by specific hepatic cytochrome P450 enzymes (Lash et al. in Environ Health Perspect 108:177-200, 2000). As association of TCE exposure with cardiac defects is in exposed embryos prior to normal liver development, we investigated metabolism of TCE in the early embryo. Developing chick embryos were dosed in ovo with environmentally relevant doses of TCE (8 and 800 ppb) and RNA was extracted from cardiac and extra-cardiac tissue (whole embryo without heart). Real-time PCR showed upregulation of CYP2H1 transcripts in response to TCE exposure in the heart. No detectable cytochrome expression was found in extra-cardiac tissue. As seen previously, the dose response was non-monotonic and 8 ppb elicited stronger upregulation than 800 ppb. Immunostaining for CYP2C subfamily expression confirmed protein expression and showed localization in both myocardium and endothelium. TCE exposure increased protein expression in both tissues. These data demonstrate that the earliest embryonic expression of phase I detoxification enzymes is in the developing heart. Expression of these CYPs is likely to be relevant to the susceptibility of the developing heart to environmental teratogens.


Assuntos
Sistema Enzimático do Citocromo P-450/biossíntese , Sistema Enzimático do Citocromo P-450/genética , Regulação Enzimológica da Expressão Gênica , Coração/efeitos dos fármacos , Coração/embriologia , Tricloroetileno/administração & dosagem , Animais , Embrião de Galinha , Relação Dose-Resposta a Droga , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Solventes/administração & dosagem
19.
J Nutr Gerontol Geriatr ; 31(3): 206-38, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22888839

RESUMO

The objective of this work is to review data from epidemiological and preclinical studies addressing the potential benefits of diets based on flavonoids for cancer prevention. Flavonoids are subdivided into subclasses including flavonols, flavones, flavanones, flavan-3-ols, anthocyanidins, and isoflavones. Epidemiological studies suggest dietary intake of flavonoids may reduce the risk of tumors of the breast, colon, lung, prostate, and pancreas. However, some studies have reported inconclusive or even harmful associations. A major challenge in the interpretation of epidemiological studies is that most of the data originate from case-control studies and retrospective acquisition of flavonoid intake. Differences in agricultural, sociodemographics, and lifestyle factors contribute to the heterogeneity in the intake of flavonoids among populations residing in the United States, Europe, and Asia. Dose and timing of exposure may influence the anticancer response to flavonoid-rich diets. A limited number of intervention trials of flavonoids have documented cancer preventative effects. Proposed anticancer mechanisms for flavonoids are inhibition of proliferation, inflammation, invasion, metastasis, and activation of apoptosis. Prospective studies with larger sample sizes are needed to develop biomarkers of flavonoid intake and effect. Mechanistic studies are needed to ascertain how flavonoid-rich diets influence gene regulation for cancer prevention.


Assuntos
Dieta , Flavonoides/uso terapêutico , Neoplasias/prevenção & controle , Fitoterapia , Extratos Vegetais/uso terapêutico , Flavonoides/efeitos adversos , Flavonoides/farmacologia , Humanos , Extratos Vegetais/efeitos adversos , Extratos Vegetais/farmacologia
20.
J Nutr Biochem ; 23(10): 1324-32, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22197621

RESUMO

Epigenetic mechanisms may contribute to reduced expression of the tumor suppressor gene BRCA-1 in sporadic breast cancers. Through environmental exposure and diet, humans are exposed to xenobiotics and food compounds that bind the aromatic hydrocarbon receptor (AhR). AhR-ligands include the dioxin-like and tumor promoter 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). The activated AhR regulates transcription through binding to xenobiotic response elements (XREs=GCGTG) and interactions with transcription cofactors. Previously, we reported on the presence of several XREs in the proximal BRCA-1 promoter and that the expression of endogenous AhR was required for silencing of BRCA-1 expression by TCDD. Here, we document that in estrogen receptor-α-positive and BRCA-1 wild-type MCF-7 breast cancer cells, the treatment with TCDD attenuated 17ß-estradiol-dependent stimulation of BRCA-1 protein and induced hypermethylation of a CpG island spanning the BRCA-1 transcriptional start site of exon-1a. Additionally, we found that TCDD enhanced the association of the AhR; DNA methyl transferase (DNMT)1, DNMT3a and DNMT3b; methyl binding protein (MBD)2; and trimethylated H3K9 (H3K9me3) with the BRCA-1 promoter. Conversely, the phytoalexin resveratrol, selected as a prototype dietary AhR antagonist, antagonized at physiologically relevant doses (1 µmol/L) the TCDD-induced repression of BRCA-1 protein, BRCA-1 promoter methylation and the recruitment of the AhR, MBD2, H3K9me3 and DNMTs (1, 3a and 3b). Taken together, these observations provide mechanistic evidence for AhR agonists in the establishment of BRCA-1 promoter hypermethylation and the basis for the development of prevention strategies based on AhR antagonists.


Assuntos
Proteína BRCA1/genética , Metilação de DNA , Inativação Gênica/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Estilbenos/farmacologia , Neoplasias da Mama/patologia , Carcinógenos/toxicidade , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Éxons , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , Células MCF-7 , Regiões Promotoras Genéticas , Receptores de Hidrocarboneto Arílico/genética , Elementos de Resposta , Resveratrol , Análise de Sequência de DNA
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