title: Induction of aromatase expression by aminoglutethimide, an aromatase inhibitor that is used to treat breast cancer in postmenopausal women.
abstract: Aromatase, a cytochrome P450, catalyzes three consecutive hydroxylation reactions converting C19 androgens to aromatic C18 estrogenic steroids. Aminoglutethimide (AG) is an aromatase inhibitor used to treat estrogen-dependent breast cancer. While AG is effective in inhibiting aromatase, it was found that aromatase activity in tumors of some breast cancer patients elevated after AG treatment (Miller and O'Neill, Steroids, 50: 245-252, 1987). These results may explain why some patients failed therapy after extensive AG treatment. Recently, we found that AG treatment increased aromatase activity in SK-BR-3, JAR, and HepG2 cell lines in a dose- and incubation time-dependent manner. AG induction is thought to occur at the transcriptional level because the aromatase mRNA level elevated after AG treatment in SK-BR-3 and HepG2 cells, as demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) analysis, and AG treatment did not increase aromatase activity in aromatase cDNA transfected cell lines (driven by the beta-actin promoter). Our primer-specific RT-PCR analysis revealed that in SK-BR-3 cells, AG enhanced the action of a promoter which is different from promoter I.1, I.3, or II. Furthermore, since the AG induction was found to be suppressed by SQ 22536, an adenylate cyclase inhibitor, a cAMP-dependent mechanism might be involved. Our study provides an insight as to why some patients fail therapy after extensive AG treatment.
authors.affiliation: Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
authors.forename: Y C
authors.initials: YC
authors.lastname: Kao
authors.forename: T
authors.initials: T
authors.lastname: Okubo
authors.forename: X Z
authors.initials: XZ
authors.lastname: Sun
authors.forename: S
authors.initials: S
authors.lastname: Chen
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000067956:Adenylyl Cyclase Inhibitors; D000616:Aminoglutethimide / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001141:Aromatase / Q000096:biosynthesis* / Q000235:genetics; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016466:CHO Cells / Q000201:enzymology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology; D002822:Choriocarcinoma / Q000201:enzymology / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004967:Estrogens; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015290:Second Messenger Systems / Q000187:drug effects; D014158:Transcription, Genetic / Q000235:genetics; D017211:Treatment Failure; D014594:Uterine Neoplasms / Q000201:enzymology / Q000473:pathology
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004967:Estrogens; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000616:Aminoglutethimide; C017759:9-(tetrahydro-2-furyl)-adenine; D000242:Cyclic AMP; D001141:Aromatase; D000225:Adenine