High-affinity anti-oestrogen binding site distinct from the oestrogen receptor

Abstract

Non-steroidal anti-oestrogens such as tamoxifen, CI 628, nafoxidine and clomiphene, are structurally related synthetic compounds that antagonize the effects of oestrogen on its target tissues, and this activity has led to the use of tamoxifen to treat advanced breast cancer. All these compounds inhibit the binding of tritiated oestradiol to cytosol from oestrogen target tissues, suggesting that anti-oestrogens bind to the oestrogen receptor. This is supported by reports that in the rat uterus and dimethyl-benz (alpha)-anthracene (DMBA)-induced rat mammary carcinoma, oestradiol and anti-oestrogens bind directly to the same number of saturable binding sites. Furthermore, oestrogens and anti-oestrogens are mutually competitive for binding to these sites. It has thus been generally accepted that the anti-oestrogens exert most of their effects through the specific oestrogen receptor. We now report a further high-affinity, anti-oestrogen binding site which may have a role in regulating the effects of non-steroidal anti-oestrogens.

Polychlorinated biphenyls induce arachidonic acid release in human platelets in a tamoxifen sensitive manner via activation of group IVA cytosolic phospholipase A2-α

“…Thus, the effects observed for anti-estrogens on CB52-induced eicosanoid formation suggest that PCBs might activate cPLA 2 -α by binding to a binding site distinct from the estrogen receptors. A high-affinity binding site for tamoxifen, distinct from the estrogen receptor has indeed been described [72]. If this binding site, or a similar is involved in PCB-induced eicosanoid formation in platelets remains to be investigated.…”

Tamoxifen, 17β-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin

“…This indicates the possible involvement of an alternative inhibitory mechanism. In this light, a type II EBS, distinct from the oestrogen receptor, was discovered (Sutherland et al, 1980) which can bind tamoxifen (although not the drug ICI 182,780) and may be induced in both oestrogen receptor negative breast cancer and melanoma cells inhibited by tamoxifen (Piantelli et al, 1995). Thus, one explanation for our data is that some of the actions of tamoxifen may have been as a result of its actions on a type II EBS rather than on a classical nuclear oestrogen binding site.…”

Binding of [3H]ethyl‐β‐carboline‐3‐carboxylate to brain benzodiazepine receptors

“…These sites may represent a distinct 'antagonist' site with a pharmacological profile similar to that of the 'agonist' site. In this regard, high affinity anti-estrogen binding sites that are distinct from the estrogen receptor itself have been reported [25].…”