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Updated: Nov 15, 2025
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Published on: August 13, 2019
Estrogen receptor alpha in the brain mediates tamoxifen-induced changes in physiology in mice
Zhi Zhang1,2, Jae Whan Park1,2, In Sook Ahn1
1Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, United States.
Abstract:
Adjuvant tamoxifen therapy improves survival in breast cancer patients. Unfortunately, long-term treatment comes with side effects that impact health and quality of life, including hot flashes, changes in bone density, and fatigue. Partly due to a lack of proven animal models, the tissues and cells that mediate these negative side effects are unclear. Here, we show that mice undergoing tamoxifen treatment experience changes in temperature, bone, and movement. Single-cell RNA sequencing reveals that tamoxifen treatment induces widespread gene expression changes in the hypothalamus and preoptic area (hypothalamus-POA). These expression changes are dependent on estrogen receptor alpha (ERα), as conditional knockout of ERα in the hypothalamus-POA ablates or reverses tamoxifen-induced gene expression. Accordingly, ERα-deficient mice do not exhibit tamoxifen-induced changes in temperature, bone, or movement. These findings provide mechanistic insight into the effects of tamoxifen on the hypothalamus-POA and indicate that ERα mediates several physiological effects of tamoxifen treatment in mice.
Insights
Tamoxifen therapy for breast cancer causes side effects by altering gene expression in the hypothalamus-POA, mediated by estrogen receptor alpha (ERα). ERα deficiency prevents these tamoxifen-induced physiological changes.
Area of Science:
- Endocrinology
- Neuroscience
- Oncology
Background:
- Adjuvant tamoxifen therapy improves breast cancer survival but causes adverse effects like hot flashes and fatigue.
- The cellular mechanisms and tissues responsible for tamoxifen's side effects are not well understood.
- Lack of suitable animal models has hindered research into tamoxifen's physiological impacts.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms underlying tamoxifen's side effects.
- To identify the specific brain regions and receptors involved in mediating tamoxifen's physiological impacts.
- To utilize a mouse model to elucidate the role of estrogen receptor alpha (ERα) in tamoxifen's effects.
Main Methods:
- Administered tamoxifen to mice and monitored physiological changes (temperature, bone density, movement).
- Performed single-cell RNA sequencing on hypothalamic and preoptic area (hypothalamus-POA) tissues.
- Utilized conditional knockout mice lacking ERα specifically in the hypothalamus-POA.
Main Results:
- Tamoxifen treatment induced significant gene expression alterations in the hypothalamus-POA.
- These gene expression changes were dependent on the presence of ERα.
- Mice lacking ERα in the hypothalamus-POA did not display tamoxifen-induced changes in temperature, bone, or movement.
- Conditional knockout of ERα in the hypothalamus-POA abolished or reversed tamoxifen's physiological effects.
Conclusions:
- Estrogen receptor alpha (ERα) in the hypothalamus-POA mediates key physiological side effects of tamoxifen.
- Tamoxifen exerts its effects through widespread gene expression changes in the hypothalamus-POA.
- These findings provide crucial mechanistic insights into tamoxifen's impact on the central nervous system and its associated side effects.
