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Hypothalamic estrogen receptor alpha mediates key side effects of tamoxifen therapy in mice

Z Zhang, J. W. Park, I. S. Ahn, G. Diamante, N. Sivakumar, D. V. Arneson, X. Yang, View ORCID ProfileJ. E. van Veen, View ORCID ProfileS. M. Correa
doi: https://doi.org/10.1101/2020.09.21.307124
Z Zhang
1Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
2Laboratory of Neuroendocrinology of the Brain Research Institute, University of California, Los Angeles, CA, USA
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J. W. Park
1Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
2Laboratory of Neuroendocrinology of the Brain Research Institute, University of California, Los Angeles, CA, USA
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I. S. Ahn
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G. Diamante
1Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
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N. Sivakumar
1Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
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D. V. Arneson
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X. Yang
1Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
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J. E. van Veen
1Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
2Laboratory of Neuroendocrinology of the Brain Research Institute, University of California, Los Angeles, CA, USA
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  • For correspondence: stephaniecorrea@ucla.edu vanveen@ucla.edu
S. M. Correa
1Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
2Laboratory of Neuroendocrinology of the Brain Research Institute, University of California, Los Angeles, CA, USA
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  • ORCID record for S. M. Correa
  • For correspondence: stephaniecorrea@ucla.edu vanveen@ucla.edu
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Abstract

Adjuvant tamoxifen therapy for invasive breast cancer improves patient survival. 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 cell types that mediate these negative side effects are largely unknown. Here we show that mice undergoing a 28-day course of tamoxifen treatment experience dysregulation of core and skin temperature, changes in bone density, and decreased physical activity, recapitulating key aspects of the human physiological response. Single cell RNA sequencing reveals that tamoxifen treatment induces significant and widespread gene expression changes in different cell types of the hypothalamus, most strongly in neurons and ependymal cells. These expression changes are dependent on estrogen receptor alpha (ERα), as conditional knockout of ERα in the hypothalamus ablated or reversed tamoxifen-induced gene expression. Accordingly, ERα-deficient mice do not exhibit changes in thermal regulation, bone density, or movement in response to tamoxifen treatment. These findings provide mechanistic insight into the effects of tamoxifen on the hypothalamus and support a model in which hypothalamic ERα mediates several key side effects of tamoxifen therapy.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://correalab.shinyapps.io/tamoxifenshiny/

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted September 21, 2020.
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Hypothalamic estrogen receptor alpha mediates key side effects of tamoxifen therapy in mice
Z Zhang, J. W. Park, I. S. Ahn, G. Diamante, N. Sivakumar, D. V. Arneson, X. Yang, J. E. van Veen, S. M. Correa
bioRxiv 2020.09.21.307124; doi: https://doi.org/10.1101/2020.09.21.307124
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Hypothalamic estrogen receptor alpha mediates key side effects of tamoxifen therapy in mice
Z Zhang, J. W. Park, I. S. Ahn, G. Diamante, N. Sivakumar, D. V. Arneson, X. Yang, J. E. van Veen, S. M. Correa
bioRxiv 2020.09.21.307124; doi: https://doi.org/10.1101/2020.09.21.307124

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