ABSTRACT
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.
Subject(s)
BRCA1 Protein/metabolism , BRCA2 Protein/metabolism , Carcinoma, Ductal, Breast/metabolism , Mutation/genetics , Animals , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Carcinoma, Ductal, Breast/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Cell Proliferation/physiology , Female , Fluorescent Antibody Technique , Germ-Line Mutation/genetics , Humans , Immunohistochemistry , Mice , T Cell Transcription Factor 1/genetics , T Cell Transcription Factor 1/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
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.
Subject(s)
Breast Neoplasms/etiology , Cell Lineage , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Gene Expression Profiling , Mammary Glands, Human/cytology , Parity/genetics , Stem Cells/cytology , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Biomarkers/metabolism , Blotting, Western , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Differentiation , Cell Proliferation , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p27/genetics , Epithelial Cells/cytology , Epithelial Cells/metabolism , Female , Fibroblasts/cytology , Fibroblasts/metabolism , Flow Cytometry , Fluorescent Antibody Technique , Humans , Immunoenzyme Techniques , Mammary Glands, Human/metabolism , Mutation/genetics , Oligonucleotide Array Sequence Analysis , Pregnancy , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Stem Cells/metabolism , Stromal Cells/cytology , Stromal Cells/metabolismABSTRACT
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.
