title: Mouse strain susceptibility to gonadectomy-induced adrenocortical tumor formation correlates with the expression of GATA-4 and luteinizing hormone receptor.
abstract: Certain inbred strains of mice, including DBA/2J, develop adrenocortical tumors in response to gonadectomy. Spindle-shaped cells with limited steroidogenic capacity, termed A cells, appear in the subcapsular region of the adrenal gland, followed by sex steroid-producing cells known as B cells. These changes result from unopposed gonadotropin production by the pituitary, but the adrenocortical factors involved in tumorigenesis have not been characterized. GATA-4, a transcription factor normally expressed in fetal, but not adult, adrenocortical cells, was found in neoplastic cells that proliferate in the adrenal cortex of gonadectomized DBA/2J mice. GATA-4 mRNA was detected in the adrenal glands of female mice 0.5 months after ovariectomy and reached a maximum by 4 months. Castrated male mice developed adrenocortical tumors more slowly than gonadectomized females, and the onset of GATA-4 expression in the adrenal was delayed. In situ hybridization and immunohistochemistry revealed GATA-4 mRNA and protein in A and B cells, but not in normal adrenocortical cells. mRNA encoding another factor associated with adrenocortical tumorigenesis, LH receptor (LHR), was detected in A and B cells. In addition, transcripts for P450 17 alpha-hydroxylase/C17-C20 lyase, an enzyme essential for the production of sex steroids, and inhibin-alpha were found in B cells. Unilateral ovarian regeneration, a phenomenon known to occur in gonadectomized mice, was observed in a subset of DBA/2J mice undergoing complete ovariectomy. In these animals, adrenocortical tumor progression was arrested; A cells and GATA-4 expression were evident, but there was no expression of LHR or P450 17 alpha-hydroxylase/C17-C20 lyase. Strain susceptibility to adrenocortical tumorigenesis (DBA/2J >> FVB/N) correlated with the expression of GATA-4 and LHR, implicating these factors in the process of adrenocortical neoplasia in response to continuous gonadotropin stimulation.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, Missouri 63110, USA.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Bielinska
authors.forename: Helka
authors.initials: H
authors.lastname: Parviainen
authors.forename: Susan B
authors.initials: SB
authors.lastname: Porter-Tinge
authors.forename: Sanne
authors.initials: S
authors.lastname: Kiiveri
authors.forename: Elena
authors.initials: E
authors.lastname: Genova
authors.forename: Nafis
authors.initials: N
authors.lastname: Rahman
authors.forename: Ilpo T
authors.initials: IT
authors.lastname: Huhtaniemi
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Muglia
authors.forename: Markku
authors.initials: M
authors.lastname: Heikinheimo
authors.forename: David B
authors.initials: DB
authors.lastname: Wilson
mesh_terms: D000302:Adrenal Cortex / Q000473:pathology / Q000503:physiopathology; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D004198:Disease Susceptibility; D005260:Female; D050991:GATA4 Transcription Factor; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009919:Orchiectomy; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology / Q000601:surgery; D012333:RNA, Messenger / Q000032:analysis; D011974:Receptors, LH / Q000235:genetics*; D012038:Regeneration; D013045:Species Specificity; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D012333:RNA, Messenger; D011974:Receptors, LH; D014157:Transcription Factors; D013254:Steroid 17-alpha-Hydroxylase