Journal
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
Volume 141, Issue -, Pages 37-43Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2013.12.020
Keywords
Aromatase inhibitor; Letrozole; Estrogen; Steroid receptor coactivator-1; Neuroendocrine; Adverse effects
Funding
- National Science Foundation of China [81171035]
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As one of the third generation of aromatase inhibitors, letrozole is a favored drug for the treatment of hormone receptor-positive breast cancer with some adverse effects on the nervous system, but the knowledge is limited and the results are controversial, the mechanism underlying its central action is also unclear. Accumulated evidences have demonstrated that estrogens derived from androgens by aromatase play profound roles in the brain through their receptors, which needs coactivator for the transcription regulation, among which steroid receptor coactivator-1 (SRC-1) has been shown to be multifunctional potentials in the brain, but whether it is regulated by letrozole is currently unknown. In this study, we examined letrozole regulation on SRC-1 expression in adult mice brain using immunohistochemistry. The results showed that letrozole induced dramatic decrease of SRC-1 in the medial septal, hippocampus, medial habenular nucleus, arcuate hypothalamic nucleus and superior colliculus (p < 0.01). Significant decrease was detected in the dorsal lateral septal nucleus, bed nucleus of stria terminalis, ventral taenia tecta, dorsomedial and ventromedial hypothalamic nuclei, dorsomedial periaqueductal gray, superior paraolivary nucleus and pontine nucleus (p < 0.05). In the hippocampus, levels of estradiol content, androgen receptor, estrogen receptor a and 13 also decreased significantly after letrozole injection. The above results demonstrated letrozole downregulation of SRC-1 in specific regions that are primarily related to learning and memory, cognition and mood, neuroendocrine as well as information integration, indicating that SRC-1 may be one important downstream central target of letrozole. Furthermore, these potential central adverse effects of letrozole should be taken into serious considerations. (C) 2014 Elsevier Ltd. All rights reserved.
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