title: Estrogen biosynthesis in human H295 adrenocortical carcinoma cells.
abstract: Adrenocortical carcinoma is an uncommon malignancy and feminizing symptoms secondary to adrenal estrogen-secretion are extremely rare. The direct secretion of estradiol by adrenocortical tumors requires, in addition to the expression of aromatase (CYP19), the expression of one or more of the reductive 17beta-hydroxysteroid dehydrogenases. The expression of CYP19 transcripts and protein were markedly induced in the H295 adrenocortical carcinoma cell line after treatment with either forskolin or vasoactive intestinal peptide (VIP). Western immunoblotting demonstrated a marked induction of the CYP19 protein of characteristic size after only a short (6h) treatment period with VIP or forskolin. The CYP19 mRNA transcripts were derived from both promoters PII (Ic) and I.3 (Id) after treatment with both agents. The reductive type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) was also constitutively expressed in the H295 cells but neither its mRNA transcript nor protein levels were altered after forskolin or VIP treatment. Western immunoblotting of an estrogen-secreting adrenal carcinoma revealed notable levels of both aromatase and AKR1C3 expression while an aldosterone-producing adrenal adenoma lacked aromatase expression and showed a reduced level of AKR1C3 expression. Immunohistochemistry of the carcinoma-bearing adrenal revealed localization of AKR1C3 not only in the tumor but also principally in the zona reticularis of the normal adrenal tissue. Adrenal aromatase and AKR1C3 expression therefore appear to be features of adrenocortical malignancies that are associated with biosynthesis of active estrogen.
authors.affiliation: Reproductive and Developmental Sciences, Centre for Reproductive Biology, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Moira R
authors.initials: MR
authors.lastname: Nicol
authors.forename: Georgia
authors.initials: G
authors.lastname: Papacleovoulou
authors.forename: Dean B
authors.initials: DB
authors.lastname: Evans
authors.forename: Trevor M
authors.initials: TM
authors.lastname: Penning
authors.forename: Mark W J
authors.initials: MW
authors.lastname: Strachan
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Johnson
authors.forename: Richard
authors.initials: R
authors.lastname: Quinton
authors.forename: J Ian
authors.initials: JI
authors.lastname: Mason
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D015096:3-Hydroxysteroid Dehydrogenases; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005576:Colforsin / Q000378:metabolism; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases; D011375:Progesterone Reductase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
chemical_list: D004967:Estrogens; D005576:Colforsin; D014660:Vasoactive Intestinal Peptide; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C533068:3 beta-hydroxysteroid dehydrogenase type II; D011375:Progesterone Reductase; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase