Genetic bases of estrogen-induced tumorigenesis in the rat: mapping of loci controlling susceptibility to mammary cancer in a Brown Norway x ACI intercross.
Exposure to estrogens is associated with an increased risk of breast cancer. Our laboratory has shown that the ACI rat is uniquely susceptible to 17beta-estradiol (E2)-induced mammary cancer. We previously mapped two loci, Emca1 and Emca2 (estrogen-induced mammary cancer), that act independently to determine susceptibility to E2-induced mammary cancer in crosses between the susceptible ACI rat strain and the genetically related, but resistant, Copenhagen (COP) rat strain. In this study, we evaluate susceptibility to E2-induced mammary cancer in a cross between the ACI strain and the unrelated Brown Norway (BN) rat strain. Whereas nearly 100% of the ACI rats developed mammary cancer when treated continuously with E2, BN rats did not develop palpable mammary cancer during the 196-day course of E2 treatment. Susceptibility to E2-induced mammary cancer segregated as a dominant or incompletely dominant trait in a cross between BN females and ACI males. In a population of 251 female (BN x ACI)F(2) rats, we observed evidence for a total of five genetic determinants of susceptibility. Two loci, Emca4 and Emca5, were identified when mammary cancer status at sacrifice was evaluated as the phenotype, and three additional loci, Emca6, Emca7, and Emca8, were identified when mammary cancer number was evaluated as the phenotype. A total of three genetic interactions were identified. These data indicate that susceptibility to E2-induced mammary cancer in the BN x ACI cross behaves as a complex trait controlled by at least five loci and multiple gene-gene interactions.
Schaffer
Beverly S
BS
Department of Genetics, Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985805 Nebraska Medical Center, Omaha, NE 68198, USA.
Lachel
Cynthia M
CM
Pennington
Karen L
KL
Murrin
Clare R
CR
Strecker
Tracy E
TE
Tochacek
Martin
M
Gould
Karen A
KA
Meza
Jane L
JL
McComb
Rodney D
RD
Shull
James D
JD
D000818:Animals; D002874:Chromosome Mapping; D003043:Cocarcinogenesis; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D020022:Genetic Predisposition to Disease; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000235:genetics; D051381:Rats; D011912:Rats, Inbred ACI; D011914:Rats, Inbred BN
D004958:Estradiol