Related Experiment Videos
Anti-oestrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts
A A Colletta1, L M Wakefield, F V Howell
1Department of Surgery, Kings College School of Medicine and Dentistry, Rayne Institute, London, UK.
Abstract:
The clinical use of anti-oestrogens in breast cancer therapy has traditionally been restricted to tumours that contain measurable oestrogen receptor protein. However, it is now widely recognised that the clinical response to adjuvant anti-oestrogen therapy appears to be independent of the oestrogen receptor content of the primary tumour. The study reported here was designed to investigate the possibility that human stromal cells can respond to anti-oestrogens by an increased synthesis of the inhibitory growth factor, transforming growth factor beta (TGF-beta). Two established human fetal fibroblast strains were used as models for the breast cancer stromal fibroblasts. These cells were found to respond to the addition of anti-oestrogens by a large increase in their synthesis of biologically active TGF-beta. Despite the application of ligand binding, immunoassay and Northern analysis, no oestrogen receptor or oestrogen receptor mRNA was detected in either of the human fetal fibroblasts strains. These observations may provide a mechanism of action of anti-oestrogens that is independent of the presence of oestrogen receptor in the tumour epithelial cells, and thus provide an explantation for the counter-intuitive results of adjuvant anti-oestrogen action.
Insights
Anti-oestrogens may treat breast cancer by stimulating stromal cells to produce growth-inhibiting transforming growth factor beta (TGF-beta), independent of tumour oestrogen receptors.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Anti-oestrogen therapy is standard for oestrogen receptor-positive breast cancer.
- Clinical response to adjuvant anti-oestrogens is independent of primary tumour oestrogen receptor (ER) levels.
- A novel mechanism for anti-oestrogen action is needed to explain this observation.
Purpose of the Study:
- To investigate if human stromal cells can increase synthesis of transforming growth factor beta (TGF-beta) in response to anti-oestrogens.
- To explore a potential ER-independent mechanism of anti-oestrogen action in breast cancer.
Main Methods:
- Two human fetal fibroblast strains were used as models for breast cancer stromal fibroblasts.
- Cells were treated with anti-oestrogens.
- TGF-beta synthesis was measured.
- Oestrogen receptor (ER) and ER mRNA were assessed using ligand binding, immunoassay, and Northern analysis.
Main Results:
- Human fetal fibroblast strains significantly increased synthesis of biologically active TGF-beta upon addition of anti-oestrogens.
- No oestrogen receptor (ER) or ER mRNA was detected in either fibroblast strain.
- This suggests an ER-independent response.
Conclusions:
- Human stromal cells can respond to anti-oestrogens by increasing TGF-beta synthesis.
- This provides a potential ER-independent mechanism for anti-oestrogen therapy in breast cancer.
- This may explain the efficacy of anti-oestrogens even in ER-negative tumours.