Tamoxifen Regulation of Bone Growth and Endocrine Function in the Ovariectomized Rat: Discrimination of Responses Involving Estrogen Receptor α/Estrogen Receptor β, G Protein-Coupled Estrogen Receptor, or Estrogen-Related Receptor γ Using Fulvestrant (ICI 182780)

Abstract

Tamoxifen is a selective estrogen receptor (ER) modulator, but it is also a deactivating ligand for estrogen-related receptor-␥ (ERR␥) and a full agonist for the G protein-coupled estrogen receptor (GPER). Fulvestrant is a selective ER down-regulator that lacks agonist effects on ER␣/ER␤, is inactive on ERR␥, but acts as a full agonist on GPER. Fulvestrant effects on tamoxifen actions on uterine and somatic growth, bone, the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis, and pituitary prolactin were analyzed to pharmacologically discriminate tamoxifen effects that may be mediated by ER␣/ER␤ versus ERR␥ versus GPER. Ovariectomized rats received tamoxifen (0.6 mg/kg/daily) plus fulvestrant at 0, 3, 6, or 12 mg/kg/daily for 5 weeks; controls received vehicle or 6 mg/kg fulvestrant daily. Tamoxifen effects to increase uterine weight, decrease serum IGF-I, increase pituitary prolactin, and increase bone mineral density could be fully blocked by fulvestrant, indicating mediation by ER␣/ER␤. Tamoxifen effects to decrease pituitary GH, tibia length, and body weight were only partially blocked by fulvestrant, indicating involvement of mechanisms unrelated to ER␣/ER␤. Fulvestrant did not inhibit tamoxifen actions to reduce total pituitary protein, again indicating effects not mediated by ER␣/ER␤. Tamoxifen actions to reduce serum GH were mimicked rather than inhibited by fulvestrant, pharmacological features consistent with GPER involvement. However, fulvestrant alone increased IGF-I and also blocked tamoxifen-evoked IGF-I decreases; thus fulvestrant effects on serum GH might reflect increased IGF-I feedback inhibition. Fulvestrant alone had no effect on the other parameters. The findings indicate that mechanisms unrelated to ER␣/ER␤ contribute to tamoxifen effects on body weight, bone growth, and pituitary function. IntroductionTamoxifen is an estrogen receptor (ER) ligand that is characterized as a selective ER modulator (SERM); it acts as estrogen agonist on some targets while acting as an antagonist or partial agonist on others. This is not attributed to differing pharmacological actions on ER␣ versus ER␤, but reflects the diversity of mechanisms mediating ER actions at different targets.In classic models of ER function, estrogen binding to the ligand-binding domain (LBD) transforms ER conformation and enhances ER binding to specific target gene DNA sequences (McDonnell et al., 2002;Smith and O'Malley, 2004). One or both of two ER transactivation domains (AF-1 and AF-2) then bind coactivator proteins that alter gene transcription via the recruitment of chromatin-remodeling complexes and other factors. AF-1 is located in the ER N terminus and is ligand-independent, whereas AF-2 in the LBD is ligand-dependent. Involvement of AF-1 or AF-2 in estrogen responses varies from target to target depending on the genes, cell types, coactivators, and other signaling systems involved.SERMs transform ER conformation in a manner that activates DNA binding and AF-1-dependent gene expression in classic models o...

Bisphenol A and its analogues disrupt centrosome cycle and microtubule dynamics in prostate cancer

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