title: Genetic bases of estrogen-induced pituitary growth in an intercross between the ACI and Copenhagen rat strains: dominant mendelian inheritance of the ACI phenotype.
abstract: Estrogens stimulate cell proliferation in a variety of tissues and are widely believed to be contributing factors in the etiology of certain cancer types in humans. The molecular mechanisms through which estrogens regulate cell proliferation are currently unknown. Estrogens stimulate proliferation of the PRL-producing lactotroph of the rat anterior pituitary gland and induce development of PRL-producing pituitary tumors in several inbred rat strains. Therefore, the lactotroph provides a well defined model for identifying the mechanisms through which estrogens regulate cell proliferation and/or survival. Data from our laboratory and others indicate that the relative sensitivity to the pituitary growth-promoting actions of estrogens is highly strain specific. This allows genetics-based approaches to be used to address the molecular mechanisms through which estrogens stimulate lactotroph proliferation and induce pituitary tumor development. In the present study we have examined the ability of diethylstilbestrol (DES) to induce pituitary growth in the genetically related AxC-Irish (ACI) and Copenhagen (COP) strains and their derived F1, F2, and backcross progeny. The data presented herein indicate that the anterior pituitary gland of the ACI strain displays approximately a 2-fold greater growth response to administered DES than does the pituitary gland of the COP strain. The average pituitary weight in male ACI rats was increased from 9.2 +/- 0.2 mg (mean +/- SD in untreated rats to 63.7 +/- 12.6 mg in rats treated with DES for 12 weeks, whereas in male COP rats, DES increased pituitary weight from 12.7 +/- 0.9 to 38.1 +/- 8.2 mg. The ACI phenotype was inherited in the F1, F2, and backcross progeny of an ACI x COP intercross as a dominant genetic trait, and the approximately 30 mg of additional pituitary growth displayed by the DES-treated ACI rat, relative to that of the treated COP rat, appeared to result from the actions of a single locus. Moreover, in F1 progeny from an ACI x Brown Norway intercross, the ACI phenotype was inherited as a dominant or incompletely dominant genetic trait. These data, when compared with findings of previous studies using the Fischer 344 rat strain, provide the first indication that distinct genetic pathways contribute to regulation of estrogen-induced pituitary growth and induction of PRL-producing pituitary tumors in the ACI and F344 rat strains.
authors.affiliation: Eppley Institute for Research in Cancer, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha 68198-6805, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Spady
authors.forename: K L
authors.initials: KL
authors.lastname: Pennington
authors.forename: R D
authors.initials: RD
authors.lastname: McComb
authors.forename: J D
authors.initials: JD
authors.lastname: Shull
mesh_terms: D000483:Alleles; D000818:Animals; D003433:Crosses, Genetic; D004054:Diethylstilbestrol / Q000633:toxicity*; D005260:Female; D005799:Genes, Dominant; D008297:Male; D010911:Pituitary Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D011388:Prolactin / Q000097:blood / Q000378:metabolism*; D051381:Rats; D011912:Rats, Inbred ACI; D011914:Rats, Inbred BN; D013045:Species Specificity
chemical_list: D004054:Diethylstilbestrol; D011388:Prolactin