Originally published as Genetics Published Articles Ahead of Print on January 31, 2005.

Genetics, Vol. 169, 2189-2197, April 2005, Copyright © 2005
doi:10.1534/genetics.104.039370

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

Tracy E. Strecker^*,, Thomas J. Spady^*,, Beverly S. Schaffer^*,, Karen A. Gould^*,, Amy E. Kaufman^*, Fangchen Shen^*, Mac T. McLaughlin^*, Karen L. Pennington^*,, Jane L. Meza and James D. Shull^*,,**,1

^* Eppley Institute for Research in Cancer, Cell Biology and Anatomy
Department of Biochemistry and Molecular Biology, Cell Biology and Anatomy
Department of Genetics, Cell Biology and Anatomy
Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-5805
^** Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5805

¹ Corresponding author: Department of Genetics, Cell Biology and Anatomy, 6005 Durham Research Center, 985805 Nebraska Medical Center, Omaha, NE 68198-5805.
E-mail: jshull{at}unmc.edu

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 F₂ 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 F₂ 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.

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