title: Methylseleninic acid is a novel suppressor of aromatase expression.
abstract: Elevated circulating estrogen levels, as a result of increased peripheral aromatization of androgens by aromatase, have been indicated to underlie the association between obesity and a higher risk of breast cancer in postmenopausal women. Although aromatase inhibitors have been used as a first-line therapy for estrogen receptor-positive breast cancer in postmenopausal women, their potential as breast cancer chemopreventive agents has been limited due to toxicities and high costs. It is therefore imperative to develop new aromatase-inhibiting/suppressing agents with lower toxicities and lower costs for breast cancer chemoprevention, especially in obese postmenopausal women. The expression of the aromatase gene, CYP19, is controlled in a tissue-specific manner by the alternate use of different promoters. In obese postmenopausal women, increased peripheral aromatase is primarily attributed to the activity of the glucocorticoid-stimulated promoter, PI.4, and the cAMP-stimulated promoter, PII. In the present study, we show that methylseleninic acid (MSA), a second-generation selenium compound, can effectively suppress aromatase activation by dexamethasone, a synthetic glucocorticoid, and forskolin, a specific activator of adenylate cyclase. Unlike the action of aromatase inhibitors, MSA suppression of aromatase activation is not mediated via direct inhibition of aromatase enzymatic activity. Rather, it is attributable to a marked downregulation of promoters PI.4- and PII-specific aromatase mRNA expression, and thereby a reduction of aromatase protein. Considering the low-cost and low-toxicity nature of MSA, our findings provide a strong rationale for the further development of MSA as a breast cancer chemopreventive agent for obese postmenopausal women.
authors: Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana 70112, USA.
authors: Ruijuan
authors: R
authors: Gao
authors: Lijuan
authors: L
authors: Zhao
authors: Xichun
authors: X
authors: Liu
authors: Brian G
authors: BG
authors: Rowan
authors: Martin
authors: M
authors: Wabitsch
authors: Dean P
authors: DP
authors: Edwards
authors: Yoshihiro
authors: Y
authors: Nishi
authors: Toshihiko
authors: T
authors: Yanase
authors: Qun
authors: Q
authors: Yu
authors: Yan
authors: Y
authors: Dong
mesh_terms: D000262:Adenylyl Cyclases / Q000737:chemistry; D017667:Adipocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D005576:Colforsin / Q000037:antagonists & inhibitors; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D010053:Ovary / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D020536:Enzyme Activators; D005938:Glucocorticoids; D009363:Neoplasm Proteins; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D011994:Recombinant Proteins; D005576:Colforsin; D003907:Dexamethasone; C008493:methylselenic acid; D001141:Aromatase; D000262:Adenylyl Cyclases