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1.
Nat Commun ; 10(1): 4182, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519911

RESUMO

Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63+TCF7+ myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues of BRCA1 germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63+TCF7+ myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression.


Assuntos
Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Carcinoma Ductal de Mama/metabolismo , Mutação/genética , Animais , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal de Mama/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Feminino , Imunofluorescência , Mutação em Linhagem Germinativa/genética , Humanos , Imuno-Histoquímica , Camundongos , Fator 1 de Transcrição de Linfócitos T/genética , Fator 1 de Transcrição de Linfócitos T/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
2.
Cell Stem Cell ; 13(1): 117-30, 2013 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-23770079

RESUMO

Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles of multiple cell types from normal breast tissue of nulliparous and parous women and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44(+) progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell-cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. We also noted a significant reduction in the frequency of CD44(+)p27(+) cells in parous women and showed, using explant cultures, that parity-related signaling pathways play a role in regulating the number of p27(+) cells and their proliferation. Our results suggest that pathways controlling p27(+) mammary epithelial cells and the numbers of these cells relate to breast cancer risk and can be explored for cancer risk assessment and prevention.


Assuntos
Neoplasias da Mama/etiologia , Linhagem da Célula , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Perfilação da Expressão Gênica , Glândulas Mamárias Humanas/citologia , Paridade/genética , Células-Tronco/citologia , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores/metabolismo , Western Blotting , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p27/genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Citometria de Fluxo , Imunofluorescência , Humanos , Técnicas Imunoenzimáticas , Glândulas Mamárias Humanas/metabolismo , Mutação/genética , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Células-Tronco/metabolismo , Células Estromais/citologia , Células Estromais/metabolismo
3.
Cancer Discov ; 2(6): 503-11, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22628410

RESUMO

BRCA1-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with basal-like subtype, whereas in the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , PTEN Fosfo-Hidrolase/genética , Proteína Supressora de Tumor p53/genética , Proteína BRCA1/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Mutação , PTEN Fosfo-Hidrolase/metabolismo , Proteína Supressora de Tumor p53/metabolismo
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