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/metabolismoRESUMO
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/metabolismoRESUMO
Primary angiosarcoma of the breast is a rare malignant tumor. We report a case of breast primary cutaneous angiosarcoma in a patient with a strong family history of malignancy. For definitive diagnosis, a tissue biopsy is needed, with immunostaining for the presence of blood vessel endothelial markers CD31 and CD34. Total mastectomy is the preferred method of surgical treatment. Chemotherapy has not been shown to increase overall survival, but in some instances it may improve local control and disease-free survival. Surgery combined with radiation may increase local control, but patients at high risk of recurrence may benefit from adjuvant treatment as well. We discuss the potential benefits from various treatments for primary cutaneous breast angiosarcoma.
