Estrogens play a central role in the regulation of cell proliferation in numerous mammalian tissues and are inextricably implicated in the etiology of several major human cancers. The prolactin (PRL)-producing lactotroph of the rat anterior pituitary gland provides a valuable model for studying regulation of cell proliferation by estrogens. It is well established that estrogens stimulate lactotroph proliferation and induce development of PRL-producing pituitary tumors in several different inbred rat strains. Clinical observations indicate that estrogens act similarly in the human anterior pituitary gland. We have demonstrated that estrogens induce pituitary tumors in F344 and ACI rats by stimulating cell proliferation and inhibiting apoptosis. A 40 percent restriction of dietary energy consumption was demonstrated to virtually abolish estrogen induced pituitary tumorigenesis in the F344 rat, not by inhibiting estrogen induce cell proliferation, but by modulating the ability of estrogen to inhibit apoptosis. Interestingly, these effects of dietary energy restriction were not observed in the ACI rat strain, strongly suggesting that different molecular mechanisms regulate lactotroph proliferation and death in the F344 and ACI rat strains. Using a genetic approach, we demonstrated that the ACI alleles of at least 2 genes act in a dominant manner to confer the pituitary growth response of the ACI rat to estrogens. Herein we propose 4 specific aims to characterize further the genetic bases of estrogen induced pituitary tumor development in the ACI rat and to begin to elucidate the molecular mechanisms through which dietary energy restriction modulates, in a rat strain specific manner, the homeostatic equilibrium between proliferation and death in the lactotroph population.
Specific Aim 1 is to define the genetic bases underlying estrogen induced pituitary tumor development in the ACI rat strain.
Specific Aim 2 is to map quantitative trait loci (QTL)that confer the tumorigenic response of the ACI rat pituitary gland to estrogen.
Specific Aim 3 is to generate congenic rat strains which carry, on the BN genetic background, ACI alleles of QTL that confer the tumorigenic response of the pituitary gland to estrogen.
Specific Aim 4 is to compare the effects of dietary energy restriction on the ability of administered estrogen to induce pituitary tumor development in F344, ACI and F344/ACI FI progeny. The research proposed herein will ultimately lead to the identification of genes that are involved in the regulation of lactotroph proliferation and death by estrogens and will reveal how the actions of these genes are modulated by dietary energy consumption. We believe that this new knowledge may have broad implications for other estrogen regulated cell populations and will thereby contribute significantly toward our efforts to prevent and treat cancers in which estrogens are etiologic factors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068529-05
Application #
2895390
Study Section
Special Emphasis Panel (ZRG2-PTHB (01))
Program Officer
Seifried, Harold E
Project Start
1995-08-15
Project End
2003-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Samanas, Nyssa Becker; Commers, Tessa W; Dennison, Kirsten L et al. (2015) Genetic etiology of renal agenesis: fine mapping of Renag1 and identification of Kit as the candidate functional gene. PLoS One 10:e0118147
Kurz, Scott G; Dennison, Kirsten L; Samanas, Nyssa Becker et al. (2014) Ept7 influences estrogen action in the pituitary gland and body weight of rats. Mamm Genome 25:244-52
Kurz, Scott G; Hansen, Kimberly K; McLaughlin, Mac T et al. (2008) Tissue-specific actions of the Ept1, Ept2, Ept6, and Ept9 genetic determinants of responsiveness to estrogens in the female rat. Endocrinology 149:3850-9
Shull, James D; Lachel, Cynthia M; Murrin, Clare R et al. (2007) Genetic control of estrogen action in the rat: mapping of QTLs that impact pituitary lactotroph hyperplasia in a BN x ACI intercross. Mamm Genome 18:657-69
Schaffer, Beverly S; Lachel, Cynthia M; Pennington, Karen L et al. (2006) Genetic bases of estrogen-induced tumorigenesis in the rat: mapping of loci controlling susceptibility to mammary cancer in a Brown Norway x ACI intercross. Cancer Res 66:7793-800
Gould, Karen A; Strecker, Tracy E; Hansen, Kimberly K et al. (2006) Genetic mapping of loci controlling diethylstilbestrol-induced thymic atrophy in the Brown Norway rat. Mamm Genome 17:451-64
Shull, James D; Lachel, Cynthia M; Strecker, Tracy E et al. (2006) Genetic bases of renal agenesis in the ACI rat: mapping of Renag1 to chromosome 14. Mamm Genome 17:751-9
Gould, Karen A; Pandey, Jyotsna; Lachel, Cynthia M et al. (2005) Genetic mapping of Eutr1, a locus controlling E2-induced pyometritis in the Brown Norway rat, to RNO5. Mamm Genome 16:854-64
Strecker, Tracy E; Spady, Thomas J; Schaffer, Beverly S et al. (2005) 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. Genetics 169:2189-97
Gould, Karen A; Tochacek, Martin; Schaffer, Beverly S et al. (2004) Genetic determination of susceptibility to estrogen-induced mammary cancer in the ACI rat: mapping of Emca1 and Emca2 to chromosomes 5 and 18. Genetics 168:2113-25

Showing the most recent 10 out of 27 publications