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Genetics, Vol. 168, 2113-2125, December 2004, Copyright © 2004
doi:10.1534/genetics.104.033878
Genetic Determination of Susceptibility to Estrogen-Induced Mammary Cancer in the ACI Rat
Mapping of Emca1 and Emca2 to Chromosomes 5 and 18
Karen A. Gould*,
,
Martin Tochacek*,
,
Beverly S. Schaffer*,,
Tanya M. Reindl*,
Clare R. Murrin*,
Cynthia M. Lachel*,,
Eric A. VanderWoude*,
Karen L. Pennington*,,
Lisa A. Flood*,
Kimberly K. Bynote,
Jane L. Meza
,
Michael A. Newton** and
James D. Shull*,,,,1
* Eppley Institute for Research in Cancer, Cell Biology and Anatomy
Department of Genetics, Cell Biology and Anatomy
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198
Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198
** Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin 53792
1 Corresponding author: Department of Genetics, Cell Biology and Anatomy, 6005 Durham Research Center, University of Nebraska Medical Center, 985805 Nebraska Medical Center, Omaha, NE 68198-5805.
E-mail: jshull{at}unmc.edu
Hormonal, genetic, and environmental factors play major roles in the complex etiology of breast cancer. When treated continuously with 17ß-estradiol (E2), the ACI rat exhibits a genetically conferred propensity to develop mammary cancer. The susceptibility of the ACI rat to E2-induced mammary cancer appears to segregate as an incompletely dominant trait in crosses to the resistant Copenhagen (COP) strain. In both (ACI x COP)F2 and (COP x ACI)F2 populations, we find strong evidence for a major genetic determinant of susceptibility to E2-induced mammary cancer on distal rat chromosome 5. Our data are most consistent with a model in which the ACI allele of this locus, termed Emca1 (estrogen-induced mammary cancer 1), acts in an incompletely dominant manner to increase both tumor incidence and tumor multiplicity as well as to reduce tumor latency in these populations. We also find evidence suggestive of a second locus, Emca2, on chromosome 18 in the (ACI x COP)F2 population. The ACI allele of Emca2 acts in a dominant manner to increase incidence and decrease latency. Together, Emca1 and Emca2 act independently to modify susceptibility to E2-induced mammary cancer.
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