RESUMO
Zinc is required for fetal development and is involved in key processes associated with breast carcinogenesis. We evaluated whether maternal zinc deficiency or supplementation during gestation influences female offspring susceptibility to breast cancer in adulthood. C57BL/6 mice consumed during gestation control (30â¯p.p.m. zinc), zinc-deficient (8 p.p.m) or zinc-supplemented (45â¯p.p.m.) diets. Maternal zinc supplementation increased in female mice offspring the incidence of chemically-induced mammary adenocarcinomas that were heavier, compared to control group. This was accompanied by a decreased number of terminal end buds, increased cell proliferation and apoptosis, and increased tumor suppressors p21, p53 and Rassf1, Zfp382 and Stat3 expression in mammary glands, as well as increased zinc status. Although maternal zinc deficiency did not alter the incidence of these lesions, it also induced heavier mammary adenocarcinomas, compared to control group. These effects were accompanied by a decreased number of terminal end buds, increased proto-oncogenes c-Myc and Lmo4 expression and H3K9Me3 and H4K20Me3 epigenetic marks in mammary glands of offspring, and decreased zinc status and increased levels of oxidative marker malondialdehyde. The data suggest that both maternal zinc deficiency and supplementation during gestation programmed increased breast cancer susceptibility in adult mice offspring following a J-shaped pattern through distinct mechanisms.
Assuntos
Deficiências Nutricionais/complicações , Suplementos Nutricionais , Neoplasias Mamárias Experimentais/etiologia , Zinco/administração & dosagem , Zinco/deficiência , Animais , Apoptose , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Masculino , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proto-Oncogenes , Proteína Supressora de Tumor p53/metabolismoRESUMO
BPA is an oestrogenic endocrine disrupting chemical compound. Exposure to BPA in as early as pregnancy leads to lifelong effects. Since endocrine and immune systems interact in a bidirectional manner, endocrine disruption may cause permanent alterations of the immune system, affecting a future anti-tumoral response. Neonate (PND 3) female syngeneic BALB/c mice were exposed to a single dose of 250 µg/kg BPA. Once sexual maturity was reached, a mammary tumour was induced injecting 4T1 cells in situ, these cells are derived from a spontaneous adenocarcinoma in a BALB/c mouse and therefore allows for an immunocompetent recipient. After 25 days of injection, showing no major endocrine alterations, BPA-exposed mice developed larger tumours. Tumour leukocytic infiltrate analysis revealed a higher proportion of regulatory T lymphocytes in the BPA-exposed group. RT-PCR analysis of tumour samples showed a decreased expression of TNF-α and IFN-γ, as well as the M2 macrophage marker Fizz-1 in the BPA-exposed group. Flow cytometry analysis revealed differences in ERα expression by T lymphocytes, macrophages and NK cells, both associated to BPA exposure and tumour development. These findings show a new aspect whereby early life BPA exposure can contribute to breast cancer development and progression by modulating the anti-tumoral immune response.
Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Neoplasias Mamárias Experimentais/etiologia , Fenóis/toxicidade , Microambiente Tumoral , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Interferon gama/genética , Interferon gama/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Background: The results of experimental studies indicate that grafting of autologous adipose tissue may induce tumorigenesis at the recipient site, but clinical results do not support a carcinogenic effect of fat grafting to the breast. Objectives: The authors assessed cancer risk following transplantation of autologous fat into murine mammary tissue. Methods: In this animal study, mammary tissues from 54 breasts of 9 female rats were either grafted with autologous subcutaneous fat, grafted with autologous omental fat, or unmanipulated. Tissues were harvested and processed for histologic and immunohistochemical analyses, and the mRNA expression levels of specific genes were determined. Results: No atypia or changes in lobular structures were observed in lipofilled breasts compared with controls. The numbers of ductal cell layers and terminal ductal units were similar for lipofilled and control breasts. Macrophage concentrations also were similar for the 3 groups. The localization and magnitude of plasminogen activator inhibitor 1 were similar for lipofilled and unmanipulated breast tissue. The percentages of cells expressing Ki67 or estrogen receptor (ER) and the ER/Ki67 balance were similar for the 3 groups. Gene expression was not altered in lipofilled breasts, compared with controls. Conclusions: No theoretical risk of cancer was detected in the microenvironment of the lipofilled rat breast.
Assuntos
Gordura Intra-Abdominal/transplante , Mamoplastia/efeitos adversos , Neoplasias Mamárias Experimentais/etiologia , Gordura Subcutânea/transplante , Transplante de Tecidos/efeitos adversos , Microambiente Tumoral , Animais , Mama/química , Mama/cirurgia , Carcinogênese , Feminino , Humanos , Imuno-Histoquímica , Gordura Intra-Abdominal/química , Gordura Intra-Abdominal/patologia , Antígeno Ki-67/análise , Omento , Inibidor 1 de Ativador de Plasminogênio/análise , Ratos , Ratos Sprague-Dawley , Medição de Risco , Gordura Subcutânea/patologia , Transplante Autólogo/efeitos adversosRESUMO
Breast cancer is a global public health problem and accumulating evidence indicates early-life exposures as relevant factors in the disease risk determination. Recent studies have shown that paternal nutrition can influence offspring health including breast cancer risk. Selenium is a micronutrient with essential role in central aspects of embryogenesis, male fertility and cancer and that has been extensively studied as a chemopreventive agent in several breast cancer experimental models. Thus, we designed an animal study to evaluate whether paternal selenium deficiency or supplementation during preconception could affect the female offspring mammary gland development and breast cancer susceptibility. Male Sprague-Dawley rats were fed AIN93-G diet containing 0.15 ppm (control diet), 0.05 ppm (deficient diet) or 1 ppm (supplemented diet) of selenium for 9 weeks and mated with control female rats. Mammary carcinogenesis was induced with 7,12-dimethylbenz[a]anthracene (DMBA) in their female offspring. Paternal selenium deficiency increased the number of terminal end buds, epithelial elongation and cell proliferation in the mammary gland of the female rat offspring and these effects were associated with higher susceptibility to DMBA-induced mammary tumors (increased incidence and higher grade tumors). On the other hand, paternal selenium supplementation did not influence any of these parameters. These results highlight the importance of father's nutrition including selenium status as a relevant factor affecting daughter's breast cancer risk and paternal preconception as a potential developmental stage to start disease preventive strategies.
Assuntos
Neoplasias Mamárias Experimentais/etiologia , Selênio/administração & dosagem , Selênio/deficiência , 9,10-Dimetil-1,2-benzantraceno , Animais , Carcinogênese , Suplementos Nutricionais , Feminino , Masculino , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , Ratos , Ratos Sprague-DawleyRESUMO
The persistent effects of animal fat consumption during pregnancy and nursing on the programming of breast cancer risk among female offspring were studied here. We have previously found that female offspring of rat dams that consumed a lard-based high-fat (HF) diet (60% fat-derived energy) during pregnancy, or during pregnancy and lactation, were at a reduced risk of developing mammary cancer. To better understand the unexpected protective effects of early life lard exposure, we have applied lipidomics and nutrigenomics approaches to investigate the fatty acid profile and global gene expression patterns in the mammary tissue of the female offspring. Consumption of this HF diet during gestation had few effects on the mammary tissue fatty acids profile of young adult offspring, while exposure from gestation throughout nursing promoted significant alterations in the fatty acids profile. Major differences were related to decreases in saturated fatty acids (SFA) and increases in omega-6 polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs) and conjugated linolenic acid (CLA) concentrations. In addition several differences in gene expression patterns by microarray analysis between the control and in utero or in utero and during lactation HF exposed offspring were identified. Differential dependency network (DDN) analysis indicated that many of the genes exhibited unique connections to other genes only in the HF offspring. These unique connections included Hrh1-Ythdf1 and Repin1-Elavl2 in the in utero HF offspring, and Rnf213-Htr3b and Klf5-Chrna4 in the in utero and lactation HF offspring, compared with the control offspring. We conclude that an exposure to a lard-based HF diet during early life changes the fatty acid profile and transcriptional network in mammary gland in young adult rats, and these changes appear to be consistent with reduced mammary cancer risk observed in our previous study.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/análise , Regulação da Expressão Gênica , Glândulas Mamárias Animais/fisiologia , Neoplasias Mamárias Experimentais/etiologia , Fatores Etários , Animais , Gorduras na Dieta , Feminino , Redes Reguladoras de Genes , Lactação , Lipídeos/análise , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos Sprague-Dawley , Fatores de RiscoRESUMO
Progesterone receptor (PR) and ErbB-2 bidirectional cross talk participates in breast cancer development. Here, we identified a new mechanism of the PR and ErbB-2 interaction involving the PR induction of ErbB-2 nuclear translocation and the assembly of a transcriptional complex in which ErbB-2 acts as a coactivator of Stat3. We also highlighted that the function of ErbB-2 as a Stat3 coactivator drives progestin-induced cyclin D1 promoter activation. Notably, PR is also recruited together with Stat3 and ErbB-2 to the cyclin D1 promoter, unraveling a new and unexpected nonclassical PR genomic mechanism. The assembly of the nuclear Stat3/ErbB-2 transcriptional complex plays a key role in the proliferation of breast tumors with functional PR and ErbB-2. Our findings reveal a novel therapeutic intervention for PR- and ErbB-2-positive breast tumors via the specific blockage of ErbB-2 nuclear translocation.
Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Neoplasias Mamárias Experimentais/etiologia , Neoplasias Mamárias Experimentais/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Fator de Transcrição STAT3/metabolismo , Transativadores/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Sequência de Bases , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Técnicas de Silenciamento de Genes , Genes bcl-1 , Humanos , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Acetato de Medroxiprogesterona/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Progestinas/toxicidade , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/genética , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Transdução de Sinais , Transcrição Gênica/efeitos dos fármacosRESUMO
Breast cancer is the most common worldwide neoplasia in women. The totality of etiology factors of breast cancer is unknown and thus an effective preventive strategy has not been developed. Risk factors associated to breast cancer can be grouped into three broad categories: a) family history (hereditary) factors, b) endocrine and reproductive factors and c) environmental and life-style factors including diet. Animal models of chemical induced mammary carcinogenesis with 7, 12-dimethylbenz[a]anthracene and N-methyl-N-nitrosourea have been useful in the study of biology, treatment and prevention of breast cancer. In this review we show the usefulness and advantages of animal models in the study of nutritional factors associated with breast cancer in order to propose new prevention strategies. We review briefly different experimental approaches as well as some physiologic effects and mechanisms of some nutritional factors studied with animal models of mammary carcinogenesis. Nutritional factors reviewed were: a) energy restriction and high-fat intake, b) soy and phytoestrogens, c) retinoids and carotenoids, d) conjugated linoleic acid, and e) brown seaweed and iodine.
Assuntos
Dieta , Modelos Animais de Doenças , Neoplasias Mamárias Experimentais , 9,10-Dimetil-1,2-benzantraceno , Animais , Carcinógenos , Carotenoides/administração & dosagem , Dieta/efeitos adversos , Dieta com Restrição de Carboidratos , Ingestão de Energia , Ácidos Graxos/administração & dosagem , Feminino , Iodo/administração & dosagem , Neoplasias Mamárias Experimentais/etiologia , Neoplasias Mamárias Experimentais/fisiopatologia , Neoplasias Mamárias Experimentais/prevenção & controle , Metilnitrosoureia , Camundongos , Ratos , Retinoides/administração & dosagem , Fatores de Risco , Alga Marinha , Glycine maxRESUMO
La mayoría de los cánceres de mama humanos son carcinomas ductales que expresan receptores hormonales, transitan por distintos estadios de hormono-dependencia y dan metástasis a distancia. No existen modelos experimentales cuyos tumores reúnan todas estas características. El modelo de inducción de carcinomas mamarios inducidos por acetato de medroxiprogesterona en el ratón, desarrollado hace años en nuestro laboratorio, es muy adecuado ya que la mayoría de los tumores inducidos son ductales, desarrollan metástasis en ganglios axilares y en pulmón, expresan altos niveles de receptores de estrógenos y progesterona cumple un rol proliferativo, mientras que en los tumores humanos, si bien cada vez hay más evidencias que sugieren que esta hormona cumple un rol importante, se les ha adjudicado a los estrógenos el rol protagónico. El objetivo de nuestras líneas de trabajo en general está orientada a jerarquizar el rol de los progestágenos en cáncer de mama. Para que un modelo experimental resulte interesante, debe reproducir en forma fidedigna la enfermedad humana y tener características intrínsecas tales como reproducibilidad, bajo costo, posibilidad de estudios in vitro, y uso de animales estándar. Nuestro modelo permite la posibilidad de diseñar estudios de carcinogénesis hormonal para evaluar cofactores que afecten el desarrollo de los tumores... (TRUNCADO)
Assuntos
Antineoplásicos Hormonais , Camundongos Endogâmicos BALB C , Carcinoma Ductal de Mama/induzido quimicamente , Carcinoma Ductal de Mama/patologia , Cariotipagem , Células Tumorais Cultivadas , Diferenciação Celular/fisiologia , Divisão Celular , Divisão Celular/fisiologia , Imuno-Histoquímica , Linhagem Celular , Modelos Animais de Doenças , Neoplasias Hormônio-Dependentes/metabolismo , Neoplasias Mamárias Experimentais/etiologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Progesterona/fisiologia , Progesterona/toxicidade , Progestinas/fisiologia , /metabolismo , Receptores de Estrogênio , Receptores de ProgesteronaRESUMO
La mayoría de los cánceres de mama humanos son carcinomas ductales que expresan receptores hormonales, transitan por distintos estadios de hormono-dependencia y dan metástasis a distancia. No existen modelos experimentales cuyos tumores reúnan todas estas características. El modelo de inducción de carcinomas mamarios inducidos por acetato de medroxiprogesterona en el ratón, desarrollado hace años en nuestro laboratorio, es muy adecuado ya que la mayoría de los tumores inducidos son ductales, desarrollan metástasis en ganglios axilares y en pulmón, expresan altos niveles de receptores de estrógenos y progesterona cumple un rol proliferativo, mientras que en los tumores humanos, si bien cada vez hay más evidencias que sugieren que esta hormona cumple un rol importante, se les ha adjudicado a los estrógenos el rol protagónico. El objetivo de nuestras líneas de trabajo en general está orientada a jerarquizar el rol de los progestágenos en cáncer de mama. Para que un modelo experimental resulte interesante, debe reproducir en forma fidedigna la enfermedad humana y tener características intrínsecas tales como reproducibilidad, bajo costo, posibilidad de estudios in vitro, y uso de animales estándar. Nuestro modelo permite la posibilidad de diseñar estudios de carcinogénesis hormonal para evaluar cofactores que afecten el desarrollo de los tumores... (TRUNCADO)(AU)
Assuntos
Neoplasias Mamárias Experimentais/etiologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/induzido quimicamente , Linhagem Celular , Diferenciação Celular/fisiologia , Divisão Celular , Divisão Celular/fisiologia , Neoplasias Hormônio-Dependentes/metabolismo , Progesterona/fisiologia , Progesterona/toxicidade , Receptores de Progesterona , Receptores de Estrogênio , Carcinoma Ductal de Mama/induzido quimicamente , Carcinoma Ductal de Mama/patologia , /fisiologia , Antineoplásicos Hormonais , Camundongos Endogâmicos BALB C , Receptor ErbB-2/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Células Tumorais Cultivadas , CariotipagemRESUMO
Una de las problemáticas más importantes del cáncer de mama es la transición de tumores de estadíos hormono-dependientes a independientes, con la consecuente insensibilidad a tratamientos hormonales. Durante los últimos años el trabajo del Laboratorio de Carcinogénesis Hormonal ha estado enfocado en el estudio de la función de los receptores de progesterona (RP) como inductores de proliferación, en el modelo experimental de cáncer de mama inducido por acetato de medroxiprogesterona (MPA) en el ratón. Así, hemos demostrado que el RP constituye un punto hacia el cual convergen varias vías estimulatorias. Nuestros datos muestran que además de por sus ligandos específicos, los RP pueden ser utilizados por factores de crecimiento tales como el FGF (Fibroblast Growth Factor) (1). Esto explicaría el porqué de la persistencia de la expresión de estos receptores en tumores que no requieren de los progestágenos para crecer y aporta datos interesantes para comprender mecanismos de plasticidad con que la célula neoplásica adopta estrategias de supervivencia que le permiten predominar sobre las normales. En este trabajo mostramos por primera vez evidencias que asocian la expresión diferencial de isoformas del RP con la capacidad de los tumores de responder al tratamiento con estradiol (E2) o antiprogestágenos en nuestro modelo experimental. Se estudiaron 6 líneas tumorales progestágeno-dependientes y 8 líneas independientes derivadas de las primeras, utilizando técnicas de "inmunoblotting"...(TRUNCADO)