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Genetic control of estrogen action in the rat: mapping of QTLs that impact pituitary lactotroph hyperplasia in a BN × ACI intercross

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Abstract

Estrogens are important regulators of growth and development and contribute to the etiology of several types of cancer. Different inbred rat strains exhibit marked, cell-type-specific differences in responsiveness to estrogens as well as differences in susceptibility to estrogen-induced tumorigenesis. Regulation of pituitary lactotroph homeostasis is one estrogen-regulated response that differs dramatically between different inbred rat strains. In this article we demonstrate that the growth response of the anterior pituitary gland of female ACI rats to 17β-estradiol (E2) markedly exceeds that of identically treated female Brown Norway (BN) rats. We further demonstrate that pituitary mass, a surrogate indicator of absolute lactotroph number, behaves as a quantitative trait in E2-treated F2 progeny generated in a genetic cross originating with BN females and ACI males. Composite interval mapping analyses of the (BN×ACI)F2 population revealed quantitative trait loci (QTLs) that exert significant effects on E2-induced pituitary growth on rat chromosome 4 (RNO4) (Ept5) and RNO7 (Ept7). Continuous treatment with E2 rapidly induces mammary cancer in female ACI rats but not BN rats, and QTLs that impact susceptibility to E2-induced mammary cancer in the (BN×ACI)F2 population described here have been mapped to RNO3 (Emca5), RNO4 (Emca6), RNO5 (Emca8), RNO6 (Emca7), and RNO7 (Emca4). Ept5 and Emca6 map to distinct regions of RNO4. However, Ept7 and Emca4 map to the same region of RNO7. No correlation between pituitary mass and mammary cancer number at necropsy was observed within the (BN×ACI)F2 population. This observation, together with the QTL mapping data, indicate that with the exception of the Ept7/Emca4 locus on RNO7, the genetic determinants of E2-induced pituitary growth differ from the genetic determinants of susceptibility to E2-induced mammary cancer.

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Acknowledgments

The authors thank Dr. Martin Tochacek, Dr. Mac McLaughlin, Ms. Amy Kaufman, Mr. Scott Kurz, Ms. Kimberly Bynoté, and Dr. Lisa Flood for their invaluable contributions to this research. This work was supported by National Institutes of Health grants R01-CA68529 (JDS) and R01-CA77876 (JDS). National Institutes of Health Cancer Center Support Grant P30-CA36727 supported shared resources within the UNMC Eppley Cancer Center. TES was supported in part by National Institutes of Health training grant T32-CA09476. BSS and TES were supported in part by training grant DAMD17-00-1-0361 from the U.S. Army Breast Cancer Training Program. BSS was supported in part by individual postdoctoral fellowship DAMD17-03-1-0477 from the U.S. Army Breast Cancer Training Program.

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Authors and Affiliations

  1. Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, 68198-5805, USA

    James D. Shull, Cynthia M. Lachel, Karen L. Pennington, Beverly S. Schaffer & Karen A. Gould

  2. Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska, 68198-5805, USA

    James D. Shull, Cynthia M. Lachel, Clare R. Murrin, Karen L. Pennington, Beverly S. Schaffer, Tracy E. Strecker & Karen A. Gould

  3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, 68198-5805, USA

    James D. Shull

  4. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, 68198-5805, USA

    Tracy E. Strecker

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  1. James D. Shull
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  2. Cynthia M. Lachel
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Correspondence to James D. Shull.

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Shull, J.D., Lachel, C.M., Murrin, C.R. et al. Genetic control of estrogen action in the rat: mapping of QTLs that impact pituitary lactotroph hyperplasia in a BN × ACI intercross. Mamm Genome 18, 657–669 (2007). https://doi.org/10.1007/s00335-007-9052-2

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  • DOI: https://doi.org/10.1007/s00335-007-9052-2

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