Nonrandom pattern of chromosome aberrations in 17β‐estradiol‐induced rat mammary tumors: Indications of distinct pathways for tumor development

Abstract

Estrogens play an important role in breast cancer etiology and the ACI rat provides a novel animal model for defining the mechanisms through which estrogens contribute to mammary cancer development. In crossing experiments between the susceptible ACI strain and two resistant strains, COP (Copenhagen) and BN (Brown Norway), several quantitative trait loci (QTL) that affect development of 17beta-estradiol (E2)-induced mammary tumors have been defined. Using comparative genomic hybridization (CGH), we have analyzed cytogenetic aberrations in E2-induced mammary cancers and have found clear patterns of nonrandom chromosomal involvement. Approximately two thirds of the tumors exhibited copy number changes. Losses of rat chromosome 5 (RNO5) and RNO20 were particularly common, and it was found that these two aberrations often occurred together. A third recurrent aberration involving proximal gain and distal loss in RNO6 probably defined a distinct subgroup of tumors, since it never occurred in combination with RNO5 loss. Interestingly, QTL with powerful effects on mammary cancer development have been mapped to RNO5 and RNO6. These findings suggest that there were at least two genetic pathways to tumor formation in this rat model of E2-induced mammary cancer. By performing CGH on mammary tumors from ACI rats, F1 rats from crosses between the ACI and COP or BN strains and ACI.BN-Emca8 congenic rats, which carry the BN allele of the Emca8 QTL on RNO5 on the ACI genetic background, we were able to determine that the constitution of the germ line influences the pattern of chromosomal aberrations.

Microalterations of Inherently Unstable Genomic Regions in Rat Mammary Carcinomas as Revealed by Long Oligonucleotide Array-Based Comparative Genomic Hybridization

“…Our previous study of E 2 -induced rat mammary carcinomas using chromosomal CGH revealed a clear pattern of nonrandom chromosomal involvement (32). Furthermore, mammary cancers induced in rats by the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine exhibited discernable somatic abnormalities (33) although distinct from chromosomal copy number changes observed in the estrogeninduced mammary tumors (32). These studies, including our present, suggest that distinct pathways may act in a carcinogen/ estrogen-specific manner and contribute to tumor development.…”

“…Thus far, only a limited number of studies have reported DNA copy number profiles of rat mammary carcinomas. Our previous study of E 2 -induced rat mammary carcinomas using chromosomal CGH revealed a clear pattern of nonrandom chromosomal involvement (32). Furthermore, mammary cancers induced in rats by the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine exhibited discernable somatic abnormalities (33) although distinct from chromosomal copy number changes observed in the estrogeninduced mammary tumors (32).…”

Mathematical modeling of carcinogenesis based on chromosome aberration data

“…Since proposed, tree models have been used by many researchers to explore the molecular mechanism of tumor development, including the CGH data from renal cell carcinoma [20,22] , hereditary breast cancers [23] , bladder cancer [24] , head and neck squamous cell cancer [25] , nasopharyngeal carcinoma [14,26] , thymoma [27] , and rat mammary tumors [28] , and breakpoint data from ovarian cancer [21] . These models have been used to identify early events, as well as marker events of subtypes of tumors, defining the sequence of these events and the involved pathways.…”

Development and characterization of a novel rat model of estrogen-induced mammary cancer

“…Concurrent treatment with tamoxifen dramatically diminishes the ability of E2 to induce mammary cancer in ACI rats, indicating an important role of ER mediated pathways in mammary tumorigenesis (Li, et al 2002; Singh, et al 2011). The mammary cancers that develop in E2 treated ACI rats express ERα and progesterone receptor (Pgr), are dependent upon estrogens for survival and growth, and exhibit non-random patterns of chromosome copy number alterations that mirror somatic copy number alterations frequently observed in breast cancers (Adamovic, et al 2007; Harvell, et al 2000; Ruhlen, et al 2009). Together, these data illustrate multiple important similarities between the mammary cancers induced by E2 in ACI rats and luminal type breast cancers in humans.…”