Differential binding of antiestrogens by rat uterine and chick oviduct cytosol

Sutherland, Robert L.; Foo, Ming San

doi:10.1016/0006-291x(79)90601-6

Cited by 80 publications

(24 citation statements)

References 12 publications

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“…The authors suggest that the concentration of free (tamoxifen) ligand is reduced such that secondary binding is not achievable, hence the sole agonist action. Similar observations have been made, for example, in cytosol extracts from chick oviduct (Sutherland & Foo 1979, Sutherland et al 1980, mature rat uterus (Faye et al 1980, Sutherland et al 1980, immature rat uterus (Sutherland et al 1980, Murphy & Sutherland 1981a, rat liver , 1986, van den Koedijk et al 1992, rat serum , guinea pig uterus (Gulino & Pasqualini 1980), calf uterus (Lerea et al 1987, ER-positive human breast carcinomas (Sutherland et al 1980, Jordan et al 1981, Murphy & Sutherland 1981a,b, Watts et al 1984, Berthois et al 1994, human follicular thyroid carcinoma cells (Gross et al 1993), and human endometrium (Sutherland et al 1980). In these tissues, a biomacromolecule was observed to bind tamoxifen and other estrogenic derivatives, including ICI 47699 (Murphy & Sutherland 1981a), and displays tissue-specific differences in cellular concentration .…”

Section: Biochemical History Of the Dual Agonist/ Antagonist Activitysupporting

confidence: 84%

Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor

Kojetin¹,

Burris²,

Jensen³

et al. 2008

Endocrine Related Cancer

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A number of studies have reported on the unusual pharmacological behavior of type I antiestrogens, such as tamoxifen. These agents display mixed agonist/antagonist activity in a dose-, cell-, and tissue-specific manner. Consequently, many efforts have been made to develop so-called 'pure' antiestrogens that lack mixed agonist/antagonist activity. The recent report of the structure of estrogen receptor (ER) b with a second molecule of 4-hydroxytamoxifen (HT) bound in the coactivator-binding surface of the ligand-binding domain (LBD) represents the first direct example of a second ER ligand-binding site and provides insight into the possible origin of mixed agonist/antagonist activity of type I antiestrogens. In this review, we summarize the biological reports leading up to the structural conformation of a second ER ligand-binding site, compare the ERb LBD structure bound with two HT molecules to other ER structures, and discuss the potential for small molecular inhibitors designed to directly inhibit ER-coactivator and, more generally, nuclear receptor (NR)-coactivator interactions. The studies support a departure from the traditional paradigm of drug targeting to the ligand-binding site, to that of a rational approach targeting a functionally important surface, namely the NR coactivator-binding (activation function-2) surface. Furthermore, we provide evidence supporting a reevaluation of the strict interpretation of the agonist/antagonist state with respect to the position of helix 12 in the NR LBD.

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Section: Biochemical History Of the Dual Agonist/ Antagonist Activitysupporting

confidence: 84%

Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor

Kojetin¹,

Burris²,

Jensen³

et al. 2008

Endocrine Related Cancer

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“…The ALBS is a member of the family of high affinity membrane-associated binding sites called anti-estrogen binding sites or AEBS (Sutherland & Foo 1979, Sutherland et al 1980) which have been identified in a variety of tissues (Gulino & Pasqualini 1982, Mehta et al 1984. A TAM resistant clone of MCF-7 cells, RTx6, differs from the parent MCF-7 cells in having no AEBS, but is identical to the parent cells with respect to the ER content and affinity (Faye et al 1987).…”

Section: The Anti-lactogen Binding Site (Albs)mentioning

confidence: 99%

Prolactin involvement in breast cancer.

Vonderhaar

1999

Endocrine-Related Cancer

121

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Normal development and differentiation of the mammary gland are profoundly influenced by prolactin (PRL). In rodent mammary cancer PRL plays a well defined role, but its role in human breast cancer has not been appreciated until recently. It is now clear that breast tissue, both normal and malignant, is a significant source of extrapituitary PRL. Thus an autocrine/paracrine role of PRL in human breast cancer may be invoked. Both PRL and PRL receptor mRNA are expressed in the vast majority of breast cancer biopsies independent of estrogen and progesterone receptor status. An autocrine/ paracrine PRL acting in human breast cancer requires that this hormone's action be blocked at the cellular level, as opposed to suppressing the synthesis and secretion of pituitary PRL. Mutants of PRL or human growth hormone are being explored which act as selective PRL antagonists. In addition, tamoxifen has been shown to act locally at the target tissue by binding directly to the PRL receptor and thus inhibiting PRL's action. These strategies may have clinical relevance in treating PRL- Endocrine-Related Cancer (1999) 6 389-404 responsive human breast cancer.

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“…These include: muscarinic receptors (Ben-Baruch et al, 1982), dopamine receptors (Hiemke & Ghraf, 1984), histamine receptors (Brandes et al, 1985), cytochromes P-450 (Ruenitz et al, 1984), calmodulin (Lam, 1984), protein kinase C (O'Brian et al, 1985) and a high affinity binding site of unknown function termed the antioestrogen binding site (AEBS) (Sutherland & Foo, 1979;Sutherland et al, 1980). The roles, if any, of these binding sites in mediating any of the effects of nonsteroidal antioestrogens, in particular their apparently non-oestrogen-receptor-mediated effects, have not been directly established, although workers in this laboratory have shown that analogues with high affinity for AEBS have more potent antiproliferative effects on breast cancer cells in vitro than analogues with low affinity for AEBS , 1985.…”

Section: Introductionmentioning

confidence: 99%

Microsomal binding sites for antioestrogens in rat liver. Properties and detergent solubilization

Watts¹,

Sutherland²

1986

Biochemical Journal

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The properties ofan antioestrogen binding site (AEBS), which has high affinity and specificity for nonsteroidal antioestrogens and structurally related compounds, have been studied in rat liver microsomes. When subcellular organelles were separated on Percoll density gradients the distribution of the AEBS paralleled that of NADPH-cytochrome c reductase, indicating that the AEBS is associated with the endoplasmic reticulum. Saturation analysis showed that [3H]tamoxifen was bound to a single class of saturable binding sites in liver microsomes with a KD of 0.9 + 0.1 nm at 0 'C. The equilibrium KD was not significantly different at 22 'C. The KD calculated from the association and dissociation rate constants for [3H]tamoxifen binding at 0 'C and 22 'C was compatible with the KD measured at equilibrium. Ligand specificity studies using tamoxifen analogues showed qualitatively similar structure-affinity relationships for the AEBS from both rat liver and the MCF 7 breast cancer cell line. In general structural modifications caused correspondingly greater changes in affinity for rat liver AEBS than for MCF 7 AEBS. The AEBS was solubilized from microsomal membranes with sodium cholate. This was the only detergent of nine tested that solubilized the site in high yield without loss of activity. Solubilization using cholate was more effective in the presence of 1 M-NaCl. In the solubilized state there was an apparent loss of [3H]tamoxifen binding activity which could be restored by dilution ofthe detergent. Gel filtration indicated an Mr of440 000-490 000 for the AEBS-cholate complex. These studies demonstrate that rat liver contains high concentrations of a microsomal AEBS which has similar properties and specificity to the AEBS previously described in human breast cancer cells. This site can be solubilized by sodium cholate to supply material suitable for further purification. INTRODUCTIONThe nonsteroidal antioestrogens, structurally related synthetic compounds, are competitive inhibitors of the binding of oestradiol to the intracellular oestrogen receptor. Numerous studies of the molecular interactions

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Differential binding of antiestrogens by rat uterine and chick oviduct cytosol

Cited by 80 publications

References 12 publications

Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor

Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor

Prolactin involvement in breast cancer.

Microsomal binding sites for antioestrogens in rat liver. Properties and detergent solubilization

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