Genetic determination of susceptibility to estrogen-induced mammary cancer in the ACI rat: mapping of Emca1 and Emca2 to chromosomes 5 and 18

Abstract

Hormonal, genetic, and environmental factors play major roles in the complex etiology of breast cancer. When treated continuously with 17beta-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)F(2) and (COP x ACI)F(2) 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)F(2) 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.

Figure 1.—

Emca1 in the (ACI × COP)F₂ population. (A) LRS values across RNO5 were derived using tumor status following 175 days of E2 treatment as the phenotype. (B) The effect of genotype at D5Rat30 on mammary tumor incidence following 175 days of E2 treatment. A 1 above a bar indicates that the incidence is significantly different from that in the ACI homozygotes. (C) The effect of genotype at D5Rat30 on mammary tumor latency and incidence. (•) Rats homozygous for the ACI allele at D5Rat30; (○) rats heterozygous at D5Rat30; (▾) rats homozygous for the COP allele at D5Rat30. (D) LRS values across RNO5 were derived using tumor multiplicity at sacrifice as the phenotype.

Figure 2.—

Emca1 in the (COP × ACI)F₂ population. (A) LRS values across RNO5 were derived using tumor status following 189 days of E2 treatment as a phenotype. (B) The effect of genotype at D5Rat53 on mammary tumor incidence following 189 days of E2 treatment. A 1 indicates that the incidence is significantly different from that in the ACI homozygotes. (C) The effect of genotype at D5Rat53 on mammary tumor latency and incidence. (•) Rats homozygous for the ACI allele at D5Rat53; (○) rats heterozygous at D5Rat53; (▾) rats homozygous for the COP allele at D5Rat53.

Figure 3.—

Emca2 in the (ACI × COP)F₂ population. (A) LRS values across RNO18 were derived using tumor status following 189 days of E2 treatment as a phenotype. (B) The effect of genotype at D18Rat21 on mammary tumor incidence following 189 days of E2 treatment. The 1 indicates that the incidence is significantly different from that in the heterozygotes. (C) The effect of genotype at D18Rat21 on mammary tumor latency and incidence. (•) Rats homozygous for the ACI allele at D18Rat21; (○) rats heterozygous at D18Rat21; (▾) rats homozygous for the COP allele at D18Rat21.

Figure 4.—

Allelic imbalance in the Emca1 interval in E2-induced mammary tumors. This figure illustrates the presence or absence of allelic imbalances at markers spanning the Emca1 interval in E2-induced mammary tumors from (ACI × COP)F₁ rats. The markers assayed are listed at the top and the position of each marker along the chromosome in centimorgans, according to the Rat Genome Database (http://rgd.mcw.edu/vcmap/), is given in parentheses. (O) The centromere. (□) Indicates that no allelic imbalance was detected at that marker in the indicated number of tumors. () Indicates that an allelic imbalance event consistent with either a loss of the COP or a gain of the ACI allele was detected at that marker in the indicated number of tumors. (▪) Indicates that an allelic imbalance event consistent with either a loss of the ACI or a gain of the COP allele was detected at that marker in the indicated number of tumors. “ND” indicates that a genotype at the indicated marker could not be determined. Map distances are not drawn to scale.

Figure 5.—

Allelic imbalance in the Emca2 interval in E2-induced mammary tumors. This figure illustrates the presence or absence of allelic imbalances at markers spanning the Emca2 interval in E2-induced mammary tumors from (ACI × COP)F₁ rats. The markers assayed are listed at the top and the position of each marker along the chromosome in centimorgans, according to the Rat Genome Database (http://rgd.mcw.edu/vcmap/), is given in parentheses. (O) The centromere. (□) Indicates that no allelic imbalance was detected at that marker in the indicated number of tumors. () Indicates that an allelic imbalance event consistent with either a loss of the COP or a gain of the ACI allele was detected at that marker in the indicated number of tumors. (▪) Indicates that an allelic imbalance event consistent with either a loss of the ACI or a gain of the COP allele was detected at that marker in the indicated number of tumors. Map distances are not drawn to scale.

Figure 6.—

Ept10 in the (ACI × COP)F₂ population. (A) LRS values across RNO1 are shown as a function of log₁₀-transformed pituitary mass. (B) The effect of genotype at D1Rat75 on pituitary mass at the time of sacrifice is illustrated. A 1 indicates that the pituitary mass is significantly different from that in the ACI homozygotes; 2 indicates that the pituitary mass is significantly different from that in the COP homozygotes.