title: Genetic bases of estrogen-induced pituitary tumorigenesis: identification of genetic loci determining estrogen-induced pituitary growth in reciprocal crosses between the ACI and Copenhagen rat strains.
abstract: Estrogens stimulate proliferation and enhance survival of the prolactin (PRL)-producing lactotroph of the anterior pituitary gland and induce development of PRL-producing pituitary tumors in certain inbred rat strains but not others. The goal of this study was to elucidate the genetic bases of estrogen-induced pituitary tumorigenesis in reciprocal intercrosses between the genetically related ACI and Copenhagen (COP) rat strains. Following 12 weeks of treatment with the synthetic estrogen diethylstilbestrol (DES), pituitary mass, an accurate surrogate marker of absolute lactotroph number, was increased 10.6-fold in ACI rats and 4.5-fold in COP rats. Composite interval mapping analyses of the phenotypically defined F(2) progeny from the reciprocal crosses identified six quantitative trait loci (QTL) that determine the pituitary growth response to DES. These loci reside on chromosome 6 [Estrogen-induced pituitary tumor (Ept)1], chromosome 3 (Ept2 and Ept6), chromosome 10 (Ept9), and chromosome 1 (Ept10 and Ept13). Together, these six Ept loci and one additional suggestive locus on chromosome 4 account for an estimated 40% of the phenotypic variance exhibited by the combined F(2) population, while 34% of the phenotypic variance was estimated to result from environmental factors. These data indicate that DES-induced pituitary mass behaves as a quantitative trait and provide information that will facilitate identification of genes that determine the tumorigenic response of the pituitary gland to estrogens.
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, 68198, USA.
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Strecker
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Spady
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Schaffer
authors.forename: Karen A
authors.initials: KA
authors.lastname: Gould
authors.forename: Amy E
authors.initials: AE
authors.lastname: Kaufman
authors.forename: Fangchen
authors.initials: F
authors.lastname: Shen
authors.forename: Mac T
authors.initials: MT
authors.lastname: McLaughlin
authors.forename: Karen L
authors.initials: KL
authors.lastname: Pennington
authors.forename: Jane L
authors.initials: JL
authors.lastname: Meza
authors.forename: James D
authors.initials: JD
authors.lastname: Shull
mesh_terms: D000818:Animals; D015415:Biomarkers; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004843:Epistasis, Genetic; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D005838:Genotype; D008297:Male; D008957:Models, Genetic; D015233:Models, Statistical; D009929:Organ Size; D010641:Phenotype; D010902:Pituitary Gland / Q000187:drug effects* / Q000473:pathology; D010911:Pituitary Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D011388:Prolactin / Q000378:metabolism; D040641:Quantitative Trait Loci; D051381:Rats; D012680:Sensitivity and Specificity; D012737:Sex Factors; D013045:Species Specificity
chemical_list: D015415:Biomarkers; D004967:Estrogens; D005819:Genetic Markers; D011388:Prolactin