daidzein and Breast-Neoplasms

Estrogen governs the regulations of various pathological and physiological actions throughout the body in both males and females. Generally, 17β-estradiol an endogenous estrogen is responsible for different health problems in pre and postmenopausal women. The major activities of endogenous estrogen are executed by nuclear estrogen receptors (ERs) ERα and ERβ while non-genomic cytoplasmic pathways also govern cell growth and apoptosis. Estrogen accomplished a fundamental role in the formation and progression of breast cancer. In this review, we have hyphenated different studies regarding ERs and a thorough and detailed study of estrogen receptors is presented. This review highlights different aspects of estrogens ranging from receptor types, their isoforms, structures, signaling pathways of ERα, ERβ and GPER along with their crystal structures, pathological roles of ER, ER ligands, and therapeutic strategies to overcome the resistance.

Topics: Breast Neoplasms; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Humans; Ligands; Male; Receptors, Estrogen

Daidzein (1) is a natural estrogenic isoflavone. We report here that 1 can be transformed into anti-estrogenic ligands by simple alkyl substitutions of the 7-hydroxyl hydrogen. To test the effect of such structural modifications on the hormonal activities of the resulting compounds, a series of daidzein analogues have been designed and synthesized. When MCF-7 cells were treated with the analogues, those resulting from hydrogen substitution by isopropyl (3d), isobutyl (3f), cyclopentyl (3g), and pyrano- (2) inhibited cell proliferation, estrogen-induced transcriptional activity, and estrogen receptor (ER) regulated progesterone receptor (PgR) gene expression. However, methyl (3a) and ethyl (3b) substitutions of the hydroxyl proton only led to moderate reduction of the estrogenic activities. These results demonstrated the structural requirements for the transformation of daidzein from an ER agonist to an antagonist. The most effective analogue, 2, was found to reduce in vivo estrogen stimulated MCF-7 cell tumorigenesis using a xenograft mouse model.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Estrogens; Female; Humans; Hydrophobic and Hydrophilic Interactions; Isoflavones; Mice; Mice, Nude; Models, Molecular; Receptors, Progesterone; Response Elements; Structure-Activity Relationship; Transcription, Genetic; Xenograft Model Antitumor Assays