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Transforming growth factor beta 1 is implicated in the failure of tamoxifen therapy in human breast cancer
A M Thompson1, D J Kerr, C M Steel
1Department of Surgery, Royal Infirmary, Edinburgh, UK.
Abstract:
Transforming growth factor-beta 1 (TGF-beta 1) is inhibitory for breast epithelial cells in vitro and treatment of breast cancer cell lines with tamoxifen results in a rise in TGF-beta 1 mRNA expression with associated inhibition of cell growth. To study whether these findings apply in vivo we examined TGF-beta 1 mRNA expression in an oestrogen-dependent mouse xenograft system following systemic treatment of the mice with tamoxifen. In agreement with in vitro studies. TGF-beta 1 mRNA expression was sustained at high levels and associated with a reduction in tumour size. A subsequent study of breast tumour tissue from 56 patients demonstrated high levels of TGF-beta 1 mRNA in 45 of the tumours. High expression was found to correlate with premenopausal status, but not with tumour oestrogen receptor content or other parameters. In a subgroup of 11 patients who had received tamoxifen therapy for 3 to 6 months prior to surgery, unexpectedly high levels of TGF-beta 1 mRNA were demonstrated in tumours increasing in size and unresponsive to tamoxifen. Data from this study indicate that in patients with breast cancer, TGF-beta 1 in the tumour may not behave as in vitro and xenograft studies have suggested. We speculate that failure of tamoxifen therapy may be due to failure of the autocrine inhibitory functions of TGF-beta 1 either alone or in combination with paracrine stimulation of stromal cells or angiogenesis and localised immunosuppression. Further studies of active TGF-beta 1, TGF-beta receptors and the interactions with other growth factors will be required to elucidate the precise role of TGF-beta 1 in human breast cancer and in the failure of tamoxifen therapy.
Insights
Transforming growth factor-beta 1 (TGF-beta 1) inhibits breast cancer growth in lab studies. However, high TGF-beta 1 in patient tumors may indicate tamoxifen resistance, suggesting complex roles in human breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Transforming growth factor-beta 1 (TGF-beta 1) inhibits breast epithelial cells in vitro.
- Tamoxifen treatment increases TGF-beta 1 mRNA expression and inhibits cell growth in breast cancer cell lines.
Purpose of the Study:
- To investigate the in vivo relevance of TGF-beta 1's role in tamoxifen-treated breast cancer.
- To examine TGF-beta 1 mRNA expression in a mouse xenograft model and human breast tumors.
Main Methods:
- Systemic tamoxifen treatment of mice with oestrogen-dependent xenografts.
- Analysis of TGF-beta 1 mRNA expression in mouse tumors and human breast tumor tissue (n=56).
- Correlation analysis with clinical parameters including menopausal status and tamoxifen therapy.
Main Results:
- In vivo mouse xenografts showed sustained high TGF-beta 1 mRNA with reduced tumor size, consistent with in vitro findings.
- High TGF-beta 1 mRNA was detected in 45 of 56 human breast tumors, correlating with premenopausal status.
- Unexpectedly high TGF-beta 1 mRNA was found in tamoxifen-resistant, growing tumors from 11 patients.
Conclusions:
- TGF-beta 1's role in human breast cancer may differ from in vitro and xenograft models.
- Tamoxifen therapy failure might stem from impaired autocrine TGF-beta 1 inhibition or paracrine effects.
- Further research on active TGF-beta 1, its receptors, and interactions is crucial for understanding its role in human breast cancer and tamoxifen resistance.