Abstract
BackgroundTamoxifen (TAM) is an important cancer therapeutic and an experimental tool for effecting genetic recombination using the inducible Cre-Lox technique. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system. This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans. A hallmark of cellular stress is induction of Activating Transcription Factor 3 (Atf3), and so to determine whether TAM induces cellular stress in the adult nervous system, we generated a knock-in mouse in which Atf3 promoter activity drives transcription of TAM-dependent Cre recombinase (Cre-ERT2); when crossed with tdtomato reporter mice, Atf3 induction results in robust and permanent genetic labeling of cells in which it is up-regulated even transiently.ResultsWe found that granular neurons of the olfactory bulb and dentate gyrus, vascular cells and ependymal cells throughout the brain, and peripheral sensory neurons expressed tdtomato in response to TAM treatment. We also show that TAM induced Atf3 up-regulation through inhibition of cholesterol epoxide hydrolase (ChEH): reporter expression was mitigated by delivery in vitamin E-rich wheat germ oil (vitamin E depletes ChEH substrates), and was partially mimicked by a ChEH-specific inhibitor.ConclusionsThis work demonstrates that TAM stresses cells of the adult central and peripheral nervous systems and highlights concerns about clinical and experimental use of TAM. We propose TAM administration in vitamin E-rich vehicles such as wheat germ oil as a simple remedy.
Highlights
Tamoxifen (TAM), a “selective estrogen receptor modulator” (SERM), is among the most widely-used anti-cancer drugs for women with estrogen receptor-positive breast tumors
When examining the resulting mice for tdtomato signal, it became clear that the ATF3-CreERT2 construct displays a small degree of TAM-independent “leakiness”
We and others have found that a small number of uninjured sensory neurons express Activating Transcription Factor 3 (Atf3) [23], and evidence of rare spontaneous recombination was found in reporterexpressing trigeminal and spinal sensory neurons, and their terminals in the spinal trigeminal nucleus and spinal cord (Fig. 1b, c)
Summary
Tamoxifen (TAM), a “selective estrogen receptor modulator” (SERM), is among the most widely-used anti-cancer drugs for women with estrogen receptor-positive breast tumors. When it binds TAM, Cre-ERT2 is translocated to the nucleus, where it can excise the stop signal, resulting in reporter expression This technique has been used in mice to permanently label newly-generated neurons in the hippocampus [8] and transiently-active neurons following exposure to novel environments [9]. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans. A hallmark of cellular stress is induction of Activating Transcription Factor 3 (Atf3), and so to determine whether TAM induces cellular stress in the adult nervous system, we generated a knock-in mouse in which Atf promoter activity drives transcription of TAM-dependent Cre recombinase (Cre-ERT2); when crossed with tdtomato reporter mice, Atf induction results in robust and permanent genetic labeling of cells in which it is up-regulated even transiently
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