Abstract

BackgroundAtypical 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.MethodsIn 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.ResultsA 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.ConclusionsThe 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.

Highlights

  • 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

  • Atypical hyperplasias (AH) tissues from two patients had both lobular and ductal characteristics and expressed levels of CDH1 mRNA similar to that in ductal lesions. These results demonstrated that the differential expression of CDH1 in lobular and ductal AH was preserved in the linear amplification and detection methods

  • We found that mRNA levels for these genes did not differ significantly between AH and histologically normal benign (HNB) in either lobular or ductal subtypes of AH

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Summary

Introduction

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. Molecular profiles of AH lesions offer insights into the earliest changes in the breast epithelium, rendering it susceptible to oncogenic transformation. Studies of premalignant breast lesions provide insights into the mechanisms rendering the breast epithelium susceptible to oncogenic transformation as well as identify interventions that could prevent breast cancer. The overall risk of developing breast cancer is increased by ~ 4-fold among women with atypia and is similar for both ductal and lobular lesions [1, 2]. Selective receptor modulators or aromatase inhibitors prevent progression of AH to invasive carcinomas by about 60% [4,5,6], further supporting an important role for estrogen signaling in malignant progression of AH

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