title: Differential regulation of estrogen receptors α and β by 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol}, a novel resveratrol analog.
abstract: Breast cancer is the second leading cause of death among women in the United States. Estrogens have been implicated as major risk factors in the development of breast neoplasms. Recent epidemiologic studies have suggested a protective role of phytoestrogens in prevention of breast and other cancers. Resveratrol, a naturally occurring phytoestrogen found notably in red grapes, berries and peanuts, has been shown to possess potent anti-cancer properties. However, the poor efficacy of resveratrol has prevented its use in a clinical setting. In order to improve the efficacy of resveratrol, we have synthesized a small combinatorial library of azaresveratrol analogs and tested them for their ability to inhibit the growth of breast cancer cell lines. We have recently shown that one of the synthesized analogs, 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol} (HPIMBD), has better anti-cancer properties than resveratrol. The objective of this study was to investigate the differential regulation of estrogen receptors (ERs) α and β as a potential mechanism of inhibition of breast cancer by HPIMBD. Estrogen receptors α and β have been shown to have opposing roles in cellular proliferation. Estrogen receptor α mediates the proliferative responses of estrogens while ERβ plays an anti-proliferative and pro-apoptotic role. We demonstrate that HPIMBD significantly induces the expression of ERβ and inhibits the expression of ERα. HPIMBD also inhibits the protein expression levels of oncogene c-Myc and cell cycle protein cyclin D1, genes downstream to ERα and important regulators of cell cycle, and cellular proliferation. HPIMBD significantly induces protein expression levels of tumor suppressors p53 and p21 in MCF-7 cells. Additionally, HPIMBD inhibits c-Myc in an ERβ-dependent fashion in MCF-10A and ERβ1-transfected MDA-MB-231 cells, suggesting regulation of ERs as an important upstream mechanism of this novel compound. Molecular docking studies confirm higher affinity for binding of HPIMBD in the ERβ cavity. Thus, HPIMBD, a novel azaresveratrol analog may inhibit the proliferation of breast cancer cells by differentially modulating the expressions of ERs α and β.
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Amruta
authors.initials: A
authors.lastname: Ronghe
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Anwesha
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Department of Genetics, School of Medicine, University of AL at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Bhupendra
authors.initials: B
authors.lastname: Singh
authors.affiliation: ISTRA, Department of Chemistry, Abeda Inamdar Senior College, University of Pune, India.
authors.forename: Prasad
authors.initials: P
authors.lastname: Dandawate
authors.affiliation: Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, University of Manitoba, Manitoba R3E0V9, Canada.
authors.forename: Leigh
authors.initials: L
authors.lastname: Murphy
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Nimee K
authors.initials: NK
authors.lastname: Bhat
authors.affiliation: ISTRA, Department of Chemistry, Abeda Inamdar Senior College, University of Pune, India.
authors.forename: Subhash
authors.initials: S
authors.lastname: Padhye
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA. Electronic address: bhath@umkc.edu.
authors.forename: Hari K
authors.initials: HK
authors.lastname: Bhat
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002396:Catechols; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000077185:Resveratrol; D012545:Schiff Bases / Q000494:pharmacology*; D013267:Stilbenes; D062366:para-Aminobenzoates / Q000494:pharmacology*
chemical_list: C580935:4-((4-hydroxyphenylimino)methyl)benzene-1,2-diol; D000970:Antineoplastic Agents; C530104:CCND1 protein, human; D002396:Catechols; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012545:Schiff Bases; D013267:Stilbenes; D062366:para-Aminobenzoates; D019938:Cyclin D1; D000077185:Resveratrol
keywords: Breast cancer; Estrogen receptors; Resveratrol; Resveratrol analogs