ABSTRACT
BACKGROUND: Atypical breast hyperplasias (AH) have a 10-year risk of progression to invasive cancer estimated at 4-7%, with the overall risk of developing breast cancer increased by ~ 4-fold. AH lesions are estrogen receptor alpha positive (ERα+) and represent risk indicators and/or precursor lesions to low grade ERα+ tumors. Therefore, molecular profiles of AH lesions offer insights into the earliest changes in the breast epithelium, rendering it susceptible to oncogenic transformation. METHODS: In this study, women were selected who were diagnosed with ductal or lobular AH, but no breast cancer prior to or within the 2-year follow-up. Paired AH and histologically normal benign (HNB) tissues from patients were microdissected. RNA was isolated, amplified linearly, labeled, and hybridized to whole transcriptome microarrays to determine gene expression profiles. Genes that were differentially expressed between AH and HNB were identified using a paired analysis. Gene expression signatures distinguishing AH and HNB were defined using AGNES and PAM methods. Regulation of gene networks was investigated using breast epithelial cell lines, explant cultures of normal breast tissue and mouse tissues. RESULTS: A 99-gene signature discriminated the histologically normal and AH tissues in 81% of the cases. Network analysis identified coordinated alterations in signaling through ERα, epidermal growth factor receptors, and androgen receptor which were associated with the development of both lobular and ductal AH. Decreased expression of SFRP1 was also consistently lower in AH. Knockdown of SFRP1 in 76N-Tert cells resulted altered expression of 13 genes similarly to that observed in AH. An SFRP1-regulated network was also observed in tissues from mice lacking Sfrp1. Re-expression of SFRP1 in MCF7 cells provided further support for the SFRP1-regulated network. Treatment of breast explant cultures with rSFRP1 dampened estrogen-induced progesterone receptor levels. CONCLUSIONS: The alterations in gene expression were observed in both ductal and lobular AH suggesting shared underlying mechanisms predisposing to AH. Loss of SFRP1 expression is a significant regulator of AH transcriptional profiles driving previously unidentified changes affecting responses to estrogen and possibly other pathways. The gene signature and pathways provide insights into alterations contributing to AH breast lesions.
Subject(s)
Gene Expression Regulation , Intercellular Signaling Peptides and Proteins/genetics , Mammary Glands, Human/metabolism , Mammary Glands, Human/pathology , Membrane Proteins/genetics , Transcriptome , Adult , Animals , Biomarkers , Biomarkers, Tumor , Breast Neoplasms/etiology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Disease Models, Animal , Disease Progression , Female , Gene Expression Profiling , Gene Regulatory Networks , Humans , Hyperplasia , Mice , Mice, Knockout , Middle Aged , Signal TransductionABSTRACT
Metabolic reprograming is a hallmark of cancer cells. However, the roles of pre-existing differences in normal cells metabolism toward cancer risk is not known. In order to assess pre-existing variations in normal cell metabolism, we have quantified the inter-individual variation in oxidative metabolism of normal primary human mammary epithelial cells (HMECs). We then assessed their response to selected cytokines such as insulin growth factor 1 (IGF1) and tumor necrosis factor alpha (TNFα), which are associated with breast cancer risk. Specifically, we compared the oxidative metabolism of HMECs obtained from women with breast cancer and without cancer. Our data show considerable inter-individual variation in respiratory activities of HMECs from different women. A bioenergetic parameter called pyruvate-stimulated respiration (PySR) was identified as a key distinguishing feature of HMECs from women with breast cancer and without cancer. Samples showing PySR over 20% of basal respiration rate were considered PySR+ve and the rest as PySR-ve . By this criterion, HMECs from tumor-affected breasts (AB) and non-tumor affected breasts (NAB) of cancer patients were mostly PySR-ve (88% and 89%, respectively), while HMECs from non-cancer patients were mostly PySR+ve (57%). This suggests that PySR-ve/+ve phenotypes are individual-specific and are not caused by field effects due to the presence of tumor. The effects of IGF1 and TNFα treatments on HMECs revealed that both suppressed respiration and extracellular acidification. In addition, IGF1 altered PySR-ve/+ve phenotypes. These results reveal individual-specific differences in pyruvate metabolism of normal breast epithelial cells and its association with breast cancer risk.
Subject(s)
Breast Neoplasms/metabolism , Energy Metabolism/drug effects , Epithelial Cells/drug effects , Insulin-Like Growth Factor I/pharmacology , Mammary Glands, Human/drug effects , Tumor Necrosis Factor-alpha/pharmacology , Adult , Aged , Cell Respiration/drug effects , Epithelial Cells/metabolism , Female , Humans , Mammary Glands, Human/metabolism , Metabolomics/methods , Middle Aged , Oxidation-Reduction , Phenotype , Pyruvic Acid/metabolism , Time Factors , Tumor Cells, Cultured , Young AdultABSTRACT
Mucoepidermoid carcinoma of the breast is a rare entity with specific morphologic and immunohistochemical features similar to its salivary gland counterpart. In the 28 reported cases to date, there has not been a comparison of the molecular characteristics of this tumor with salivary gland mucoepidermoid carcinomas. Herein, a case of mucoepidermoid carcinoma of the breast with a molecular alteration similar to its salivary gland counterpart is reported. A lymph node metastasis was identified despite a predominantly in situ component and foci of microinvasion. The morphologic, immunohistochemical, prognostic, and molecular features are discussed.
