Genetic Determination of Susceptibility to Estrogen-Induced Mammary Cancer in the ACI Rat

Abstract

Hormonal, genetic, and environmental factors play major roles in the complex etiology of breast cancer. When treated continuously with 17␤-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 ϫ COP)F 2 and (COP ϫ 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 (e strogen-induced m ammary ca ncer 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 ϫ 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.

Exposure to estrogen and ionizing radiation causes epigenetic dysregulation, activation of mitogen-activated protein kinase pathways, and genome instability in the mammary gland of ACI rats

“…[44][45][46][47][48] Considering that few other rat strains exhibit this propensity to develop mammary cancer in response to continuous E 2 treatment, it appears that the ACI rat possesses a unique genetic and epigenetic background that underlies its susceptibility to elevated estrogen levels. [49][50][51] Furthermore, the ACI rat has low levels of spontaneous and radiation-induced mammary tumors, thus it is an ideal model to analyze the combined effects of radiation and estrogen.…”

Isolation of two regions on rat chromosomes 5 and 18 affecting mammary cancer susceptibility

“…26 This QTL, Emca1 limited by the markers D5Rat53 and D5Rat57, was defined in a cross involving the susceptible strain ACI and the resistant strain COP. 26 It overlaps the distal part of Mcs5 and Mcstm1 (Fig. 1), but it might be distinct from Mcs5 (and Mcstm1) because no QTL associated with chromosome 5 was found to control susceptibility to DMBA-induced mammary tumors in a cross between WF and COP.…”

“…Emca1 also controls tumor latency, 26 while Mcs5 has not been reported to do so. 25,32 The congenic strain SPRD-Cu3.WKY-Mcstm2, which is characterized by the presence of the Mcstm2 QTL on chromosome 18 exhibits a 33% reduction in tumor multiplicity when compared with animals of the parental strain SPRD-Cu3.…”

“…26 This QTL (named Emca1), limited by the markers D5Rat53 and D5Rat57, was defined in a cross involving the susceptible strain ACI and the resistant strain COP. 26 Mcstm1 and Emca1 share the region limited by the markers D5Rat53 (position: 103,682 kb) and D5Rat57 (position: 155,131 kb).…”

“…26 This QTL (named Emca1), limited by the markers D5Rat53 and D5Rat57, was defined in a cross involving the susceptible strain ACI and the resistant strain COP. 26 Mcstm1 and Emca1 share the region limited by the markers D5Rat53 (position: 103,682 kb) and D5Rat57 (position: 155,131 kb). Using a similar haplotype sharing approach, we sought for markers the alleles of which would be identical two by two, in the two susceptible strains ACI and SPRD-Cu3, and in the resistant ones, Cop and WKY.…”