{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:58:17Z","timestamp":1791305897490,"version":"4.3.1"},"reference-count":52,"publisher":"The Endocrine Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,2,1]]},"abstract":"<jats:p>Postgonadectomy adrenocortical tumorigenesis is a strain-specific phenomenon in inbred mice, assumed to be caused by elevated LH secretion and subsequent ectopic LH receptor (LHR) overexpression in adrenal gland. However, the molecular mechanisms of this cascade of events remain unknown. In this study, we took advantage of the mouse strain dependency of the phenotype to unravel its genetic basis. Our results present the first genome-wide screening related to this pathology in two independent F2 and backcross populations generated between the neoplastic DBA\/2J and the nonsusceptible C57BL\/6J strains. Surprisingly, the postgonadectomy elevation of serum LH was followed by similar up-regulation of adrenal LHR expression in both parental strains and their crosses, irrespective of their tumor status, indicating that it is not the immediate cause of the tumorigenesis. Linkage analysis revealed one major significant locus for the tumorigenesis on chromosome 8, modulated by epistasis with another quantitative trait locus on chromosome 18. Weight gain, a secondary phenotype after gonadectomy, showed a significant but separate quantitative trait locus on chromosome 7. Altogether, postgonadectomy adrenocortical tumorigenesis in DBA\/2J mice is a dominant trait that is not a direct consequence of adrenal LHR expression but is driven by a complex genetic architecture. Analysis of candidate genes in the tumorigenesis linkage region showed that Sfrp1 (secreted frizzled-related protein 1), a tumor suppressor gene, is differentially expressed in the neoplastic areas. These findings may have relevance to the human pathogenesis of macronodular adrenal hyperplasia and adrenocortical tumors in postmenopausal women and why some of them develop obesity.<\/jats:p>","DOI":"10.1210\/en.2007-0925","type":"journal-article","created":{"date-parts":[[2007,11,16]],"date-time":"2007-11-16T01:47:17Z","timestamp":1195177637000},"page":"651-661","source":"Crossref","is-referenced-by-count":48,"title":["Adrenal Gland Tumorigenesis after Gonadectomy in Mice Is a Complex Genetic Trait Driven by Epistatic Loci"],"prefix":"10.1210","volume":"149","author":[{"given":"Sophie","family":"Bernichtein","sequence":"first","affiliation":[{"name":"Department of Reproductive Biology (S.B., S.J., I.T.H.), Medical Research Council, Clinical Sciences Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Petretto","sequence":"first","affiliation":[{"name":"Division of Epidemiology (E.P.), Public Health and Primary Care"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey","family":"Jamieson","sequence":"first","affiliation":[{"name":"Department of Reproductive Biology (S.B., S.J., I.T.H.), Medical Research Council, Clinical Sciences Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuj","family":"Goel","sequence":"first","affiliation":[{"name":"Physiological Genomics and Medicine Group (E.P., A.G., T.J.A., J.M.M.), Medical Research Council, Clinical Sciences Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Aitman","sequence":"first","affiliation":[{"name":"Physiological Genomics and Medicine Group (E.P., A.G., T.J.A., J.M.M.), Medical Research Council, Clinical Sciences Center"},{"name":"Section of Molecular Genetics and Rheumatology (T.J.A.), Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Mangion","sequence":"first","affiliation":[{"name":"Physiological Genomics and Medicine Group (E.P., A.G., T.J.A., J.M.M.), Medical Research Council, Clinical Sciences Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilpo T.","family":"Huhtaniemi","sequence":"first","affiliation":[{"name":"Department of Reproductive Biology (S.B., S.J., I.T.H.), Medical Research Council, Clinical Sciences Center"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2007,11,15]]},"reference":[{"key":"2020071613003238800_R1","first-page":"637","article-title":"A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology.","volume":"85","author":"Mantero","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613003238800_R2","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1097\/00001622-200301000-00013","article-title":"Adrenal incidentaloma.","volume":"15","author":"Thompson","year":"2003","journal-title":"Curr Opin Oncol"},{"key":"2020071613003238800_R3","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1093\/ajcp\/67.4.318","article-title":"Ovarian thecal metaplasia in adrenal glands.","volume":"67","author":"Fidler","year":"1977","journal-title":"Am J Clin Pathol"},{"key":"2020071613003238800_R4","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1210\/jcem-38-1-126","article-title":"A gonadotropin-responsive adrenocortical adenoma.","volume":"38","author":"Givens","year":"1974","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613003238800_R5","first-page":"1071","article-title":"Thecal metaplasia in the adrenal gland of a man with acquired bilateral testicular atrophy.","volume":"113","author":"Romberger","year":"1989","journal-title":"Arch Pathol Lab Med"},{"key":"2020071613003238800_R6","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1097\/00001622-200201000-00011","article-title":"Adrenal incidentalomas.","volume":"14","author":"Bertherat","year":"2002","journal-title":"Curr Opin Oncol"},{"key":"2020071613003238800_R7","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.tem.2004.08.007","article-title":"Cushing\u2019s syndrome variants secondary to aberrant hormone receptors.","volume":"15","author":"Lacroix","year":"2004","journal-title":"Trends Endocrinol Metab"},{"key":"2020071613003238800_R8","first-page":"119","article-title":"Clinical and subclinical ACTH-independent macronodular adrenal hyperplasia and aberrant hormone receptors.","volume":"64","author":"Christopoulos","year":"2005","journal-title":"Horm Res"},{"key":"2020071613003238800_R9","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1080\/gye.16.5.413.417","article-title":"Pregnancy-associated Cushing\u2019s syndrome secondary to a luteinizing hormone\/human chorionic gonadotropin receptor-positive adrenal carcinoma.","volume":"16","author":"Wy","year":"2002","journal-title":"Gynecol Endocrinol"},{"key":"2020071613003238800_R10","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1354\/vp.43-2-97","article-title":"Gonadectomy-induced adrenocortical neoplasia in the domestic ferret (Mustela putorius furo) and laboratory mouse.","volume":"43","author":"Bielinska","year":"2006","journal-title":"Vet Pathol"},{"key":"2020071613003238800_R11","first-page":"1667","article-title":"Gonadectomy permits adrenocortical tumorigenesis in mice transgenic for the mouse inhibin \u03b1-subunit promoter\/simian virus 40 T-antigen fusion gene: evidence for negative autoregulation of the inhibin \u03b1-subunit gene.","volume":"10","author":"Kananen","year":"1996","journal-title":"Mol Endocrinol"},{"key":"2020071613003238800_R12","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1172\/JCI7716","article-title":"Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex.","volume":"105","author":"Kero","year":"2000","journal-title":"J Clin Invest"},{"key":"2020071613003238800_R13","doi-asserted-by":"crossref","first-page":"3975","DOI":"10.1210\/en.2004-1643","article-title":"Gonadotropin-induced adrenocortical neoplasia in NU\/J nude mice.","volume":"146","author":"Bielinska","year":"2005","journal-title":"Endocrinology"},{"key":"2020071613003238800_R14","doi-asserted-by":"crossref","first-page":"4123","DOI":"10.1210\/en.2003-0126","article-title":"Mouse strain susceptibility to gonadectomy-induced adrenocortical tumor formation correlates with the expression of GATA-4 and luteinizing hormone receptor.","volume":"144","author":"Bielinska","year":"2003","journal-title":"Endocrinology"},{"key":"2020071613003238800_R15","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1210\/me.2002-0282","article-title":"Adrenocortical tumorigenesis in transgenic mice expressing the inhibin \u03b1-subunit promoter\/simian virus 40 T-antigen transgene: relationship between ectopic expression of luteinizing hormone receptor and transcription factor GATA-4.","volume":"18","author":"Rahman","year":"2004","journal-title":"Mol Endocrinol"},{"key":"2020071613003238800_R16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1084\/jem.74.1.1","article-title":"Histological changes following ovariectomy in mice.","volume":"74","author":"Fekete","year":"1941","journal-title":"J Exp Med"},{"key":"2020071613003238800_R17","first-page":"193","article-title":"The incidence of adrenal cortical carcinoma in gonadectomized female mice of the extreme dilution strain.","volume":"5","author":"Woolley","year":"1945","journal-title":"Cancer Res"},{"key":"2020071613003238800_R18","first-page":"1211","article-title":"Postcastrational adrenal tumors in two strains of mice: morphologic, histochemical, and chromatographic studies.","volume":"45","author":"Krishna Murthy","year":"1970","journal-title":"J Natl Cancer Inst"},{"key":"2020071613003238800_R19","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1210\/endo.132.4.8462469","article-title":"A supersensitive immunofluorometric assay for rat luteinizing hormone.","volume":"132","author":"Haavisto","year":"1993","journal-title":"Endocrinology"},{"key":"2020071613003238800_R20","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1677\/joe.0.1210409","article-title":"Effect of short-term starvation on reproductive hormone gene expression, secretion and receptor levels in male rats.","volume":"121","author":"Bergendahl","year":"1989","journal-title":"J Endocrinol"},{"key":"2020071613003238800_R21","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1073\/pnas.84.8.2363","article-title":"Construction of multilocus genetic linkage maps in humans.","volume":"84","author":"Lander","year":"1987","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613003238800_R22","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/S0888-7543(05)80158-2","article-title":"Systematic detection of errors in genetic linkage data.","volume":"14","author":"Lincoln","year":"1992","journal-title":"Genomics"},{"key":"2020071613003238800_R23","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1093\/bioinformatics\/btg112","article-title":"R\/qtl: QTL mapping in experimental crosses.","volume":"19","author":"Broman","year":"2003","journal-title":"Bioinformatics"},{"key":"2020071613003238800_R24","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1093\/genetics\/138.3.963","article-title":"Empirical threshold values for quantitative trait mapping.","volume":"138","author":"Churchill","year":"1994","journal-title":"Genetics"},{"key":"2020071613003238800_R25","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1093\/genetics\/151.1.373","article-title":"Statistical methods for mapping quantitative trait loci from a dense set of markers.","volume":"151","author":"Dupuis","year":"1999","journal-title":"Genetics"},{"key":"2020071613003238800_R26","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1093\/genetics\/139.3.1421","article-title":"A nonparametric approach for mapping quantitative trait loci.","volume":"139","author":"Kruglyak","year":"1995","journal-title":"Genetics"},{"key":"2020071613003238800_R27","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1093\/genetics\/163.3.1169","article-title":"Mapping quantitative trait loci in the case of a spike in the phenotype distribution.","volume":"163","author":"Broman","year":"2003","journal-title":"Genetics"},{"key":"2020071613003238800_R28","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/hdy.1992.131","article-title":"A simple regression method for mapping quantitative trait loci in line crosses using flanking markers.","volume":"69","author":"Haley","year":"1992","journal-title":"Heredity"},{"key":"2020071613003238800_R29","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1007\/s00335-004-2326-z","article-title":"Sex- and lineage-specific inheritance of depression-like behavior in the rat.","volume":"15","author":"Solberg","year":"2004","journal-title":"Mamm Genome"},{"key":"2020071613003238800_R30","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s00335-005-0170-4","article-title":"A comprehensive mouse IBD database for the efficient localization of quantitative trait loci.","volume":"17","author":"Cervino","year":"2006","journal-title":"Mamm Genome"},{"key":"2020071613003238800_R31","author":"Lynch","year":"1998"},{"key":"2020071613003238800_R32","doi-asserted-by":"crossref","first-page":"3951","DOI":"10.1128\/MCB.23.11.3951-3964.2003","article-title":"Activin induces x-zone apoptosis that inhibits luteinizing hormone-dependent adrenocortical tumor formation in inhibin-deficient mice.","volume":"23","author":"Beuschlein","year":"2003","journal-title":"Mol Cell Biol"},{"key":"2020071613003238800_R33","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1210\/jc.2005-1975","article-title":"Aberrant expression of human luteinizing hormone receptor by adrenocortical cells is sufficient to provoke both hyperplasia and Cushing\u2019s syndrome features.","volume":"91","author":"Mazzuco","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613003238800_R34","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1210\/en.2005-0921","article-title":"Ectopic expression of the gastric inhibitory polypeptide receptor gene is a sufficient genetic event to induce benign adrenocortical tumor in a xenotransplantation model.","volume":"147","author":"Mazzuco","year":"2006","journal-title":"Endocrinology"},{"key":"2020071613003238800_R35","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1081\/ERC-200044149","article-title":"Transcription factors GATA-4 and GATA-6 in human adrenocortical tumors.","volume":"30","author":"Kiiveri","year":"2004","journal-title":"Endocr Res"},{"key":"2020071613003238800_R36","first-page":"954","article-title":"Differences in adrenal responsiveness to postcastrational alteration as evidenced by transplanted adrenal tissue.","volume":"11","author":"Huseby","year":"1951","journal-title":"Cancer Res"},{"key":"2020071613003238800_R37","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1677\/joe.0.1410033","article-title":"Adrenocortical dysplasia: a mouse model system for adrenocortical insufficiency.","volume":"141","author":"Beamer","year":"1994","journal-title":"J Endocrinol"},{"key":"2020071613003238800_R38","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1093\/hmg\/ddi011","article-title":"Urogenital and caudal dysgenesis in adrenocortical dysplasia (acd) mice is caused by a splicing mutation in a novel telomeric regulator.","volume":"14","author":"Keegan","year":"2005","journal-title":"Hum Mol Genet"},{"key":"2020071613003238800_R39","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S1525-1578(10)60517-X","article-title":"Allelic imbalance of 8p indicates poor survival in gastric cancer.","volume":"6","author":"French","year":"2004","journal-title":"J Mol Diagn"},{"key":"2020071613003238800_R40","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/sj.ijo.0802516","article-title":"Multiple linked mouse chromosome 7 loci influence body fat mass.","volume":"28","author":"Diament","year":"2004","journal-title":"Int J Obes Relat Metab Disord"},{"key":"2020071613003238800_R41","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1006\/geno.1997.4835","article-title":"Obesity QTLs on mouse chromosomes 2 and 17.","volume":"43","author":"Taylor","year":"1997","journal-title":"Genomics"},{"key":"2020071613003238800_R42","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1007\/s00125-007-0700-6","article-title":"Fatty liver and obesity: phenotypically correlated but genetically distinct traits in a mouse model of type 2 diabetes.","volume":"50","author":"Itoi-Babaya","year":"2007","journal-title":"Diabetologia"},{"key":"2020071613003238800_R43","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1086\/512133","article-title":"No gene is an island: the flip-flop phenomenon.","volume":"80","author":"Lin","year":"2007","journal-title":"Am J Hum Genet"},{"key":"2020071613003238800_R44","doi-asserted-by":"crossref","first-page":"6770","DOI":"10.1073\/pnas.94.13.6770","article-title":"Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action.","volume":"94","author":"Finch","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613003238800_R45","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/nrg1427","article-title":"WNT and \u03b2-catenin signalling: diseases and therapies.","volume":"5","author":"Moon","year":"2004","journal-title":"Nat Rev Genet"},{"key":"2020071613003238800_R46","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1038\/sj.onc.1209386","article-title":"Aberrant methylation of the Wnt antagonist SFRP1 in breast cancer is associated with unfavourable prognosis.","volume":"25","author":"Veeck","year":"2006","journal-title":"Oncogene"},{"key":"2020071613003238800_R47","doi-asserted-by":"crossref","first-page":"5680","DOI":"10.1038\/sj.onc.1210345","article-title":"Frequent loss of SFRP1 expression in multiple human solid tumours: association with aberrant promoter methylation in renal cell carcinoma.","volume":"26","author":"Dahl","year":"2007","journal-title":"Oncogene"},{"key":"2020071613003238800_R48","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1677\/joe.1.06750","article-title":"Gonadectomy in mice of the inbred strain CE\/J induces proliferation of sub-capsular adrenal cells expressing gonadal marker genes.","volume":"190","author":"Johnsen","year":"2006","journal-title":"J Endocrinol"},{"key":"2020071613003238800_R49","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1677\/joe.0.1110477","article-title":"The streaming adrenal cortex: direct evidence of centripetal migration of adrenocytes by estimation of cell turnover rate.","volume":"111","author":"Zajicek","year":"1986","journal-title":"J Endocrinol"},{"issue":"Pt 2","key":"2020071613003238800_R50","first-page":"375","article-title":"Cell proliferation and renewal of mouse adrenal cortex","volume":"188","author":"Kataoka","year":"1996","journal-title":"J Anat"},{"key":"2020071613003238800_R51","doi-asserted-by":"crossref","first-page":"2848","DOI":"10.1210\/me.2006-0182","article-title":"Origin and identity of adrenocortical tumors in inhibin knockout mice: implications for cellular plasticity in the adrenal cortex.","volume":"20","author":"Looyenga","year":"2006","journal-title":"Mol Endocrinol"},{"key":"2020071613003238800_R52","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/sj.cr.7290260","article-title":"Wnt signaling in disease and in development.","volume":"15","author":"Nusse","year":"2005","journal-title":"Cell Res"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/149\/2\/651\/8996991\/endo0651.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/149\/2\/651\/8996991\/endo0651.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T22:39:06Z","timestamp":1630103946000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/149\/2\/651\/2454833"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,11,15]]},"references-count":52,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2008,2,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2007-0925","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,11,15]]}}}