Identification of molecular distinctions between normal breast-associated fibroblasts and breast cancer-associated fibroblasts

Andrea Sadlonova, Damon B. Bowe, Zdenek Novak, Shibani Mukherjee, Virginia E. Duncan, Grier P. Page, Andra R. Frost

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Stromal fibroblasts influence the behavior of breast epithelial cells. Fibroblasts derived from normal breast (NAF) inhibit epithelial growth, whereas fibroblasts from breast carcinomas (CAF) have less growth inhibitory capacity and can promote epithelial growth. We sought to identify molecules that are differentially expressed in NAF versus CAF and potentially responsible for their different growth regulatory abilities. To determine the contribution of soluble molecules to fibroblast-epithelial interactions, NAF were grown in 3D, transwell or direct contact co-cultures with MCF10AT epithelial cells. NAF suppressed proliferation of MCF10AT in both direct contact and transwell co-cultures, but this suppression was significantly greater in direct co-cultures, indicating involvement of both soluble and contact factors. Gene expression profiling of early passage fibroblast cultures identified 420 genes that were differentially expressed in NAF versus CAF. Of the eight genes selected for validation by real-time PCR, FIBULIN 1, was overexpressed in NAF, and DICKKOPF 1, NEUREGULIN 1, PLASMINOGEN ACTIVATOR INHIBITOR 2, and TISSUE PLASMINOGEN ACTIVATOR were overexpressed in CAF. A higher expression of FIBULIN 1 in normal- than cancer-associated fibroblastic stroma was confirmed by immunohistochemistry of breast tissues. Among breast cancers, stromal expression of Fibulin 1 protein was higher in estrogen receptor α-positive cancers and low stromal expression of Fibulin 1 correlated with a higher proliferation of cancer epithelial cells. In conclusion, expression profiling of NAF and CAF cultures identified many genes with potential relevance to fibroblast-epithelial interactions in breast cancer. Furthermore, these early passage fibroblast cultures can be representative of gene expression in stromal fibroblasts in vivo.

Original languageEnglish (US)
Pages (from-to)9-21
Number of pages13
JournalCancer Microenvironment
Volume2
Issue number1
DOIs
StatePublished - Jan 2009

Fingerprint

Breast
Fibroblasts
Breast Neoplasms
Coculture Techniques
Epithelial Cells
Growth
Plasminogen Activator Inhibitor 2
Neuregulin-1
Genes
Neoplasms
Cancer-Associated Fibroblasts
Gene Expression Profiling
RNA Interference
Estrogen Receptors
Real-Time Polymerase Chain Reaction
Immunohistochemistry
Gene Expression
Proteins

Keywords

  • Breast cancer
  • Fibroblasts
  • Fibulin 1
  • Gene expression profiling
  • Stroma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Identification of molecular distinctions between normal breast-associated fibroblasts and breast cancer-associated fibroblasts. / Sadlonova, Andrea; Bowe, Damon B.; Novak, Zdenek; Mukherjee, Shibani; Duncan, Virginia E.; Page, Grier P.; Frost, Andra R.

In: Cancer Microenvironment, Vol. 2, No. 1, 01.2009, p. 9-21.

Research output: Contribution to journalArticle

Sadlonova, Andrea ; Bowe, Damon B. ; Novak, Zdenek ; Mukherjee, Shibani ; Duncan, Virginia E. ; Page, Grier P. ; Frost, Andra R. / Identification of molecular distinctions between normal breast-associated fibroblasts and breast cancer-associated fibroblasts. In: Cancer Microenvironment. 2009 ; Vol. 2, No. 1. pp. 9-21.
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