Clinical and functional significance of loss of caveolin-1 expression in breast cancer-associated fibroblasts

Samantha A Simpkins, Andrew M Hanby, Deborah L Holliday, Valerie Speirs

Research output: Contribution to journalArticle

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Abstract

Loss of caveolin-1 (Cav-1) expression in breast cancer-associated fibroblasts (CAFs) is predictive of poor prognosis in breast cancer, but its function has not been established. Our study tested the hypotheses that loss of Cav-1 expression in breast fibroblasts was associated with poor prognosis in breast cancer, through promotion of breast cancer cell invasion. Cav-1 stromal expression was immunohistochemically assessed in 358 breast cancers. Cav-1 expression in primary breast fibroblasts was analysed by western blot. Modified Boyden chamber assays determined fibroblast ability to promote invasion of breast cancer cells. The impact of siRNA silencing of Cav-1 in fibroblasts was evaluated using invasion assays and 3D co-culture assays. Loss of Cav-1 expression in breast stroma was significantly associated with decreased breast cancer-specific and disease-free survival (p = 0.01). Mean survival was 72 months (Cav-1(+) group) versus 29.5 months (Cav-1(-) group). This was confirmed in multivariate analysis. Cav-1 expression was significantly decreased in CAFs compared to normal fibroblasts (p = 0.01) and was associated with increased invasion-promoting capacity. Cav-1 siRNA-treated fibroblasts promoted significantly increased invasion of MDA-MB-468 and T47D breast cancer cells from 27% (control) to 67% (p = 0.006) and from 37% to 56%, respectively (p = 0.01). 3D co-cultures of MDA-MB-468 cells with myoepithelial cells led to the formation of organized cohesive structures when cultured with conditioned media from fibroblasts but resulted in a disorganized appearance in the presence of conditioned media from Cav-1 siRNA-treated fibroblasts, accompanied by loss of E-cadherin expression in tumour cells. Our data confirm that loss of stromal Cav-1 in breast cancer predicts poor outcome. At a functional level, Cav-1-deficient CAFs are capable of significantly increasing the invasive capacity of breast cancer cells.

Original languageEnglish
Pages (from-to)490-8
Number of pages9
JournalThe Journal of pathology
Volume227
Issue number4
Early online date4 Apr 2012
DOIs
Publication statusPublished - Aug 2012

Fingerprint

Caveolin 1
Breast Neoplasms
Fibroblasts
Small Interfering RNA
Breast
Conditioned Culture Medium
Coculture Techniques
Cancer-Associated Fibroblasts
Breast Diseases
Cadherins
Disease-Free Survival

Keywords

  • Biomarkers, Tumor
  • Breast Neoplasms
  • Cadherins
  • Caveolin 1
  • Cell Line, Tumor
  • Cells, Cultured
  • Disease-Free Survival
  • Down-Regulation
  • Female
  • Fibroblasts
  • Humans
  • In Vitro Techniques
  • Middle Aged
  • Prognosis
  • RNA, Small Interfering
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Clinical and functional significance of loss of caveolin-1 expression in breast cancer-associated fibroblasts. / Simpkins, Samantha A; Hanby, Andrew M; Holliday, Deborah L; Speirs, Valerie.

In: The Journal of pathology, Vol. 227, No. 4, 08.2012, p. 490-8.

Research output: Contribution to journalArticle

Simpkins, Samantha A ; Hanby, Andrew M ; Holliday, Deborah L ; Speirs, Valerie. / Clinical and functional significance of loss of caveolin-1 expression in breast cancer-associated fibroblasts. In: The Journal of pathology. 2012 ; Vol. 227, No. 4. pp. 490-8.
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