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SFRP1-regulated gene expression in premalignant breast lesions

ABSTRACT: • Atypical hyperplasias (AH) provide insights into early changes that may predispose breast epithelial cells to oncogenic transformation. • Of genes associated with premalignancy in prior studies, only mRNA levels of ESR1 and SFRP1 were detected in the present study. • Transcriptional profiling defined signatures distinguishing atypical hyperplasias. The patterns of expression were similar among hyperplastic lesions of lobular and ductal phenotype suggesting a common set of alterations underlying both lesions. Pathway analyses identified elevated expression of estrogen receptor alpha, androgen receptor and EGFR receptors and Rho signaling as central events nodes in the pathways altered in AH. • A set of 43 genes were identified as common targets using 2 different algorithms to detect signatures associated with AH. Knockdown of SFRP1 in a TERT immortalized breast epithelial cell line resulted in 14 genes from this signature being either up-regulated or down-regulated as observed in the expression profiles from AH. • The results demonstrate a signature of genes representing alterations that are common to the development of hyperplasias in both ductal and lobular epithelium. Loss of SFRP1 expression is a key player underlying the transcriptional changes in AH that directs a module of genes that can be used to improve reproducibility of diagnosis of AH.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118432 | GEO | 2020/04/10

REPOSITORIES: GEO

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Project description:The identification of genomic alterations occurring in neoplastic lesions provides insight into both lesion occurrence and disease progression. In this study we used microarray comparative genomic hybridization (CGH) to investigate genetic changes in atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), as the presence of these lobular neoplastic lesions is an indicator of risk in the development of invasive breast cancer. DNA was extracted from microdissected archival breast tissue containing ALH or LCIS, lacking adjacent invasive carcinoma, and subjected to whole-genome tiling path microarray-CGH using the submegabase resolution tiling set (SMRTr)-array platform. Twelve ALH and 13 LCIS lesions were examined. Copy number alterations were identified using statistical criteria and validated with Real-Time PCR and fluorescence in situ hybridization. From statistical analysis, a greater number of alterations were observed in ALH compared to LCIS. Alterations common to ALH include gain at 2p11.2 and loss at 7p11.2-p11.1 and 22q11.1. Alterations common to LCIS include gain at 20q13.13 and loss at 19q13.2-q13.31. In both ALH and LCIS, we observed loss of 16q21-q23.1, an altered region previously identified in lobular neoplasia and invasive carcinoma. The validation of select alterations reinforces the genomic signature. This study represents the first whole-genome investigation of lobular neoplastic breast lesions using clinical archival specimens. The identified genomic signature includes copy number alterations not previously identified for lobular neoplasia. This genomic signature, common to ALH and LCIS, suggests a role for the acquisition of novel genomic alterations in the aberrant cellular proliferation that defines lobular neoplasia. Keywords: comparative genomic hybridization, high resolution analysis of atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) human archival breast lesions by whole genome tiling path array CGH

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SFRP1-regulated gene expression in premalignant breast lesions

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