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In vivo inhibition of insulin-like growth factor I gene expression by tamoxifen
H T Huynh1, E Tetenes, L Wallace
1Department of Medicine, McGill University, Montréal, Québec, Canada.
Abstract:
Tamoxifen, a partial antagonist to the estrogen receptor, is widely used in the treatment of breast cancer and is currently being evaluated as a breast cancer preventative agent in large-scale clinical trials. Recent clinical research has demonstrated that tamoxifen administration is associated with a reduction of serum insulin-like growth factor I (IGF-I) concentration. We demonstrate here that tamoxifen, when administered in an in vivo experimental system previously used to demonstrate its cytostatic effect on breast cancer cell proliferation, inhibits the expression of the IGF-I gene in common target organs for breast cancer metastasis. Furthermore, while our prior experimental studies have demonstrated an inhibitory effect of tamoxifen on growth hormone output, we show here for the first time that the suppression of IGF-I gene expression associated with tamoxifen administration is in part a consequence of a pituitary-independent action of the drug. Because IGF-I is a potent mitogen for breast cancer cells, this newly described activity of tamoxifen may contribute to its antineoplastic properties, particularly with regard to inhibition of metastasis seen both in animal models and clinically.
Insights
Tamoxifen reduces insulin-like growth factor I (IGF-I) gene expression in breast cancer metastasis targets. This pituitary-independent action may contribute to tamoxifen's anti-cancer effects.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Tamoxifen is an estrogen receptor antagonist used for breast cancer treatment and prevention.
- Clinical studies show tamoxifen reduces serum insulin-like growth factor I (IGF-I) levels.
- IGF-I promotes breast cancer cell proliferation and metastasis.
Purpose of the Study:
- To investigate tamoxifen's effect on IGF-I gene expression in vivo.
- To determine if tamoxifen's suppression of IGF-I is pituitary-dependent or independent.
- To explore the contribution of IGF-I suppression to tamoxifen's antineoplastic activity.
Main Methods:
- Administered tamoxifen in an established in vivo breast cancer model.
- Assessed IGF-I gene expression in target organs of metastasis.
- Evaluated the role of the pituitary in tamoxifen-induced IGF-I suppression.
Main Results:
- Tamoxifen inhibited IGF-I gene expression in breast cancer metastasis target organs.
- This suppression was partly due to a pituitary-independent action of tamoxifen.
- Tamoxifen previously shown to inhibit growth hormone output.
Conclusions:
- Tamoxifen directly inhibits IGF-I gene expression in vivo.
- A novel pituitary-independent mechanism contributes to tamoxifen's effects.
- Reduced IGF-I may enhance tamoxifen's efficacy against breast cancer growth and metastasis.