ABSTRACT
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
Immunostaining for thyroid transcription factor-1 (TTF-1) is frequently used to help assess the site of origin of metastatic carcinomas. TTF-1 expression is most frequently seen in carcinomas of thyroid and lung origin. Furthermore, it has been assumed that the expression of TTF-1 in a carcinoma excludes the possibility of a breast origin. We have recently encountered in our consultation practice 4 cases of invasive breast carcinoma (confirmed by clinical findings and other immunophenotypic features) that showed unequivocal tumor cell expression of TTF-1. However, the frequency with which TTF-1 expression is observed in breast carcinomas is unknown. To address this, we carried out immunostaining for TTF-1 on 546 primary breast carcinomas submitted for routine estrogen receptor, progesterone receptor, and/or HER2 testing. Cases were considered TTF-1 positive if they showed any nuclear staining for this marker. TTF-1 expression was identified in 13 cases (2.4%). Expression varied from focal and weak to diffuse and strong and was seen in both invasive and in situ components. We conclude that a small proportion of breast carcinomas show TTF-1 expression. Therefore, the presence of TTF-1 immunoreactivity in a carcinoma cannot by itself be used to exclude the possibility of a breast origin.
