Format

Send to

Choose Destination
Breast Cancer Res. 2019 Jun 27;21(1):76. doi: 10.1186/s13058-019-1157-5.

Gene expression signature of atypical breast hyperplasia and regulation by SFRP1.

Author information

1
Pioneer Valley Life Sciences Institute, Springfield, MA, 01199, USA.
2
Department of Veterinary and Animal Sciences, University of Massachusetts-Amherst, Amherst, MA, 01003, USA.
3
Department of Mathematics and Statistics, University of Massachusetts, Amherst, MA, 01003, USA.
4
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
5
Department of Pathology, University of Massachusetts Medical School/Baystate, Springfield, MA, 01199, USA.
6
Division of Hematology-Oncology, University of Massachusetts Medical School/Baystate, Springfield, MA, 01107, USA.
7
Department of Surgery, University of Massachusetts Medical School/Baystate, Springfield, MA, 01199, USA.
8
University of Massachusetts Medical School, Molecular, Cell, and Cancer Biology, Worcester, MA, 01605, USA.
9
Department of Pathology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
10
Pioneer Valley Life Sciences Institute, Springfield, MA, 01199, USA. Sallie.Schneider@baystatehealth.org.
11
Department of Veterinary and Animal Sciences, University of Massachusetts-Amherst, Amherst, MA, 01003, USA. Sallie.Schneider@baystatehealth.org.
12
Pioneer Valley Life Sciences Institute, Springfield, MA, 01199, USA. jjerry@vasci.umass.edu.
13
Department of Veterinary and Animal Sciences, University of Massachusetts-Amherst, Amherst, MA, 01003, USA. jjerry@vasci.umass.edu.

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.

KEYWORDS:

Atypical hyperplasia; Breast; Ductal; Gene expression profile; Lobular; Premalignancy; SFRP1

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center