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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Tamoxifen administration to mice
Jonathan Whitfield1, Trevor Littlewood2, Laura Soucek1
1Vall d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain; Universitat Autònoma de Barcelona, 08193 Bellaterra (Cerdanyola del Vallès), Spain;
Abstract:
The strategy of fusing a protein of interest to a hormone-binding domain (HBD) of a steroid hormone receptor allows fine control of the activity of the fused protein. Such fusion proteins are inactive in the absence of ligand, because they are complexed with a variety of intracellular polypeptides. Upon ligand binding, the receptor is released from its inhibitory complex and the fusion protein becomes functional. In the murine estrogen receptor (ER) fusion system, proteins are fused to the HBD of the ER. The system relies on the use of a mutant ER known as ER(TAM). Compared to the wild-type HBD, ER(TAM) has 1000-fold lower affinity for estrogen, yet remains responsive to activation by the synthetic steroid 4-hydroxytamoxifen (4-OHT). Because 4-OHT is expensive, animals can be treated with the cheaper precursor tamoxifen, which is converted into 4-OHT by a liver enzyme. Here we present an overview of the methods used to deliver tamoxifen to mice. The most used method is intraperitoneal injection, because the amount of administered compound can be better controlled, but delivery by oral gavage is also possible. For short-term and immediate-effect studies or when conversion of tamoxifen by the liver is to be avoided, 4-OHT can be used directly.
Insights
Researchers explored tamoxifen delivery methods in mice for controlling fused protein activity. Intraperitoneal injection offers better dose control than oral gavage for tamoxifen-based systems.
Area of Science:
- Molecular Biology
- Endocrinology
- Pharmacology
Background:
- Fusion proteins with hormone-binding domains (HBDs) offer inducible control over protein activity.
- The murine estrogen receptor (ER) fusion system utilizes a mutant ER (ER(TAM)) with low estrogen affinity but high sensitivity to 4-hydroxytamoxifen (4-OHT).
- Tamoxifen is a precursor to 4-OHT, requiring hepatic conversion, making it a cost-effective alternative for in vivo studies.
Purpose of the Study:
- To provide an overview of tamoxifen administration methods in mice for ER fusion systems.
- To compare the efficacy and control offered by different tamoxifen delivery routes.
Main Methods:
- Review of established methods for tamoxifen delivery in murine models.
- Comparison of intraperitoneal injection and oral gavage for tamoxifen administration.
- Consideration of direct 4-OHT administration for specific experimental designs.
Main Results:
- Intraperitoneal injection is the preferred method for precise tamoxifen dose control.
- Oral gavage is a viable alternative delivery route.
- Direct 4-OHT administration bypasses hepatic metabolism for immediate effects.
Conclusions:
- Tamoxifen delivery methods significantly impact the control and timing of ER fusion protein activation in mice.
- Choice of delivery route (intraperitoneal injection vs. oral gavage) depends on experimental requirements for dose accuracy.
- Direct 4-OHT use is suitable for studies requiring rapid, metabolism-independent induction.
