Gene expression signature of atypical breast hyperplasia and regulation by SFRP1

Autor: Jacob P. S. Johnson, D. Joseph Jerry, Ben R. Schneider, Karl Simin, Giovanna M. Crisi, Sallie S. Schneider, Ashraf Khan, Lihua Julie Zhu, Jacob A. Mayfield, Holly Mason, Kelly J. Gregory, Mary J. Hagen, Erin M. Conlon, Grace Makari-Judson, Jeffrey J. Kane, Amy L. Roberts, Brooke A. Bentley, Jun Yu
Rok vydání: 2018
Předmět:
Adult
Atypical hyperplasia
Breast Neoplasms
Biology
lcsh:RC254-282
Lobular
03 medical and health sciences
Mice
0302 clinical medicine
Breast cancer
Premalignancy
Gene expression
Progesterone receptor
Ductal
medicine
Biomarkers
Tumor
Animals
Humans
Gene Regulatory Networks
Breast
skin and connective tissue diseases
Mammary Glands
Human
Mice
Knockout
Gene knockdown
Hyperplasia
Gene Expression Profiling
Membrane Proteins
Gene signature
Middle Aged
Gene expression profile
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
3. Good health
Androgen receptor
Disease Models
Animal
Gene Expression Regulation
030220 oncology & carcinogenesis
Cancer research
Disease Progression
SFRP1
Intercellular Signaling Peptides and Proteins
Female
Transcriptome
Estrogen receptor alpha
Biomarkers
Signal Transduction
Research Article
Zdroj: Breast Cancer Research : BCR
Breast Cancer Research, Vol 21, Iss 1, Pp 1-18 (2019)
ISSN: 1465-542X
Popis: 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. Electronic supplementary material The online version of this article (10.1186/s13058-019-1157-5) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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