title: Characterization of the weak estrogen receptor alpha agonistic activity of exemestane.
abstract: Third generation aromatase inhibitors (AI) have shown good clinical efficacy in comparison to the anti-estrogen tamoxifen. The steroidal AI, exemestane (EXE) has previously been shown to act as an androgen, but this report demonstrates the estrogen-like activity of EXE. Based on genome-wide microarray analysis, high correlation was seen between EXE-Only (EXE O, hormone-free) and hormone-containing AI-resistant lines. In addition, the top regulated genes in the EXE O lines were mostly estrogen-responsive genes. This estrogen-like activity of EXE was further validated using estrogen receptor (ER) activity assays, where in comparison to 17beta-estradiol (E2), EXE was able to induce ER activity, though at a higher concentration. Also, this EXE-mediated ER activity was blocked by the ER antagonist ICI as well as the ERalpha-specific antagonist methyl-piperidino-pyrazole (MPP). Similarly, EXE was able to induce proliferation of breast cancer cell lines, MCF-7 and MCF-7aro, as well as activate transcription of known estrogen-responsive genes, i.e., PGR, pS2 and AREG. These results suggest that EXE does have weak estrogen-like activity.
authors.affiliation: Department of Surgical Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Selma
authors.initials: S
authors.lastname: Masri
authors.forename: Ki
authors.initials: K
authors.lastname: Lui
authors.forename: Sheryl
authors.initials: S
authors.lastname: Phung
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ye
authors.forename: Dujin
authors.initials: D
authors.lastname: Zhou
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Shiuan
authors.initials: S
authors.lastname: Chen
mesh_terms: D000077384:Anastrozole; D000730:Androstadienes / Q000494:pharmacology*; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D046228:Microarray Analysis; D009570:Nitriles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014230:Triazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; D047628:Estrogen Receptor alpha; D009570:Nitriles; D012333:RNA, Messenger; D014230:Triazoles; D000077384:Anastrozole; C056516:exemestane