title: GATA4 is a critical regulator of gonadectomy-induced adrenocortical tumorigenesis in mice.
abstract: In response to gonadectomy certain inbred mouse strains develop sex steroidogenic adrenocortical neoplasms. One of the hallmarks of neoplastic transformation is expression of GATA4, a transcription factor normally present in gonadal but not adrenal steroidogenic cells of the adult mouse. To show that GATA4 directly modulates adrenocortical tumorigenesis and is not merely a marker of gonadal-like differentiation in the neoplasms, we studied mice with germline or conditional loss-of-function mutations in the Gata4 gene. Germline Gata4 haploinsufficiency was associated with attenuated tumor growth and reduced expression of sex steroidogenic genes in the adrenal glands of ovariectomized B6D2F1 and B6AF1 mice. At 12 months after ovariectomy, wild-type B6D2F1 mice had biochemical and histological evidence of adrenocortical estrogen production, whereas Gata4(+/-) B6D2F1 mice did not. Germline Gata4 haploinsufficiency exacerbated the secondary phenotype of postovariectomy obesity in B6D2F1 mice, presumably by limiting ectopic estrogen production in the adrenal glands. Amhr2-cre-mediated deletion of floxed Gata4 (Gata4(F)) in nascent adrenocortical neoplasms of ovariectomized B6.129 mice reduced tumor growth and the expression of gonadal-like markers in a Gata4(F) dose-dependent manner. We conclude that GATA4 is a key modifier of gonadectomy-induced adrenocortical neoplasia, postovariectomy obesity, and sex steroidogenic cell differentiation.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, Missouri 63110, USA.
authors.forename: Justyna
authors.initials: J
authors.lastname: Krachulec
authors.forename: Melanie
authors.initials: M
authors.lastname: Vetter
authors.forename: Anja
authors.initials: A
authors.lastname: Schrade
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Löbs
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Bielinska
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cochran
authors.forename: Antti
authors.initials: A
authors.lastname: Kyrönlahti
authors.forename: Marjut
authors.initials: M
authors.lastname: Pihlajoki
authors.forename: Helka
authors.initials: H
authors.lastname: Parviainen
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Jay
authors.forename: Markku
authors.initials: M
authors.lastname: Heikinheimo
authors.forename: David B
authors.initials: DB
authors.lastname: Wilson
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism* / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D057895:Haploinsufficiency; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D004967:Estrogens; D050991:GATA4 Transcription Factor