Antagonism of oestrogen action in human breast and endometrial cells in vitro: potential novel antitumour agents

• Published in: Cancer chemotherapy and pharmacology Vol. 47; no. 5; pp. 437 - 443
• Main Authors: NUTTALL, Mark E, PENDRAK, Israil, EMERY, John G, NADEAU, Daniel P, FISHER, Paul W, NICHOLSON, Thema A, YUAN ZHU, SUVA, Larry J, KINGSBURY, William D, GOWEN, Maxine
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01-05-2001
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Breast Neoplasms - metabolism; Cell Division - drug effects; Chemotherapy; Endometrium - cytology; Endometrium - drug effects; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogen Antagonists - pharmacology; Female; Fulvestrant; Gene Expression Regulation, Neoplastic - drug effects; Humans; Medical sciences; Neoplasms, Hormone-Dependent - metabolism; Pharmacology. Drug treatments; Receptors, Estrogen - drug effects; Tumor Cells, Cultured - drug effects; Antineoplastic agent; Human; Cell proliferation; Ligand; Antiestrogen; Estrogen; Chemical structure; Malignant tumor; In vitro; Biological activity; Mammary gland diseases; Binding capacity; Analog; Established cell line; Antagonist; Mammary gland; Sex steroid hormone; Tumor cell; Endometrium; Hormonal receptor
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s002800000259

There is a need to find novel oestrogen receptor (ER) ligands that antagonize oestrogen action in the reproductive tissues and would therefore have therapeutic potential in oestrogen-dependent tumours. We tested novel ER ligands in both breast and endometrial cells to profile agonism/antagonism in these oestrogen target reproductive tissues.
Novel analogues of the ER antagonist ICI 182,780 were synthesized and tested for their ability to inhibit gene expression dependent on oestrogen response elements (ERE) in human breast (MCF-7) and endometrial (Ishikawa) cell lines. This activity was correlated with inhibition of oestrogen-induced cell proliferation and ER binding.
The sulphide analogue (compound 1) and sulphone analogue (compound 2) had no intrinsic ERE-dependent agonism in either breast cancer or endometrial cells in culture. All three compounds dose-dependently inhibited ERE-mediated oestrogen agonism. Moreover, these ER ligands inhibited oestrogen-stimulated proliferation of breast cancer and endometrial cells. ICI 182,780, compound 1 and compound 2 were all able to bind both isoforms of the ER (ER alpha and ER beta). In endometrial cells, the relative binding to ER beta correlated with the ERE-dependent antioestrogenic effect of these ligands, suggesting that in this tissue this receptor is the predominant isoform that determines antioestrogenic activity.
The ability of these analogues of ICI 182,780 to inhibit oestrogen-stimulated transcriptional activity and cell proliferation suggests that these agents, in particular the sulphone analogue, have therapeutic potential in the treatment of breast cancer without exhibiting the unwanted oestrogenic effects in the endometrium.