There are two homologous nuclear receptors for the hormone 17β-estradiol (estrogen), commonly called ERα and ERβ. Receptor activation leads to the formation of homo- and hetero-dimers, which in turn interact with accessory proteins to regulate gene transcription. Tamoxifen is a selective estrogen receptor modulator, evoking tissue-dependent effects. It is an antagonist of ER action in breast tissue and breast cancer cells and is reported to be effective in the treatment of early breast cancer to prevent tumor growth.^1,2 Importantly, tamoxifen has been reported to act as an ER agonist in bone and blood vessels, helping to minimize osteoporosis and reduce the risk of cardiovascular disease in post-menopausal women.³ Also, tamoxifen is a partial ER agonist in uterine tissues and is reported to increase the risk of endometrial carcinoma.⁴

1 Horwitz, K.B., and McGuire, W.L. Nuclear mechanisms of estrogen action. Effects of estradiol and anti-estrogens on estrogen receptors and nuclear receptor processing. J Biol Chem 253(22) 8185-8191 (1978).

2 Clarke, M., Collins, R., Davies, C., et al. Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351 1451-1467 (1998).

3 Tonetti, D.A., and Jordan, V.C. Targeted anti-estrogens to treat and prevent diseases in women. Mol Med Today 218-223 (1996).

4 Jordan, V.C., and Assikis, V.J. Endometrial carcinoma and tamoxifen: Clearing up a controversy. Clin Cancer Res 1 467-472 (1995).

Tonetti, D.A., and Jordan, V.C. Targeted anti-estrogens to treat and prevent diseases in women. Mol Med Today 218-223 (1996).

Kim, H.P., Lee, J.Y., Jeong, J.K., et al. Nongenomic stimulation of nitric oxide release by estrogen is mediated by estrogen receptor α localized in caveolae. Biochem Biophys Res Commun 263 257-262 (1999).

Paech, K., Webb, P., Kuiper, G.G.J.M., et al. Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 277 1508-1510 (1997).

Hall, J.M., Couse, J.F., and Korach, K.S. The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem 276(40) 36869-26872 (2001).

Henderson, B.E., and Feigelson, H.S. Hormonal carcinogenesis. Carcinogenesis 21(3) 427-433 (2000).

Renodon, A., Boucher, J., Sari, M., et al. Strong inhibition of neuronal nitric oxide synthase by the calmodulin antagonist and anti-estrogen drug tamoxifen. Biochem Pharmacol 54 1109-1114 (1997).

Zhu, Y., Qi, C., Jain, S., et al. Amplification and overexpression of peroxisome proliferator-activated receptor binding protein (PBP/PPARBP) gene in breast cancer. Proc Natl Acad Sci USA 96 10848-10853 (1999).

Clarke, M., Collins, R., Davies, C., et al. Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351 1451-1467 (1998).

Jordan, V.C., and Assikis, V.J. Endometrial carcinoma and tamoxifen: Clearing up a controversy. Clin Cancer Res 1 467-472 (1995).

Horwitz, K.B., and McGuire, W.L. Nuclear mechanisms of estrogen action. Effects of estradiol and anti-estrogens on estrogen receptors and nuclear receptor processing. J Biol Chem 253(22) 8185-8191 (1978).

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