title: Validation of six genetic determinants of susceptibility to estrogen-induced mammary cancer in the rat and assessment of their relevance to breast cancer risk in humans.
abstract: When treated with 17β-estradiol, female ACI rats (Rattus norvegicus) rapidly develop mammary cancers that share multiple phenotypes with luminal breast cancers. Seven distinct quantitative trait loci that harbor genetic determinants of susceptibility to 17β-estradiol-induced mammary cancer have been mapped in reciprocal intercrosses between susceptible ACI rats and resistant Brown Norway (BN) rats. A panel of unique congenic rat strains has now been generated and characterized to confirm the existence of these quantitative trait loci, designated Emca3 through Emca9, and to quantify their individual effects on susceptibility to 17β-estradiol-induced mammary cancer. Each congenic strain carries BN alleles spanning an individual Emca locus, introgressed onto the ACI genetic background. Data presented herein indicate that BN alleles at Emca3, Emca4, Emca5, Emca6, and Emca9 reduce susceptibility to 17β-estradiol-induced mammary cancer, whereas BN alleles at Emca7 increase susceptibility, thereby confirming the previous interval mapping data. All of these Emca loci are orthologous to regions of the human genome that have been demonstrated in genome-wide association studies to harbor genetic variants that influence breast cancer risk. Moreover, four of the Emca loci are orthologous to loci in humans that have been associated with mammographic breast density, a biomarker of breast cancer risk. This study further establishes the relevance of the ACI and derived congenic rat models of 17β-estradiol-induced mammary cancer for defining the genetic bases of breast cancer susceptibility and elucidating the mechanisms through which 17β-estradiol contributes to breast cancer development.
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706-1599.
authors.forename: John A
authors.initials: JA
authors.lastname: Colletti
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706-1599 Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5805.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Leland-Wavrin
authors.affiliation: Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5805.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Kurz
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706-1599.
authors.forename: Maureen Peters
authors.initials: MP
authors.lastname: Hickman
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706-1599.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Seiler
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706-1599.
authors.forename: Nyssa Becker
authors.initials: NB
authors.lastname: Samanas
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706-1599.
authors.forename: Quincy A
authors.initials: QA
authors.lastname: Eckert
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706-1599.
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: Dennison
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706-1599.
authors.forename: Lina
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5805.
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Schaffer
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706-1599 Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5805 shull@oncology.wisc.edu.
authors.forename: James D
authors.initials: JD
authors.lastname: Shull
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D004958:Estradiol; D004967:Estrogens; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000235:genetics*; D010641:Phenotype; D040641:Quantitative Trait Loci; D011914:Rats, Inbred BN; D012306:Risk
chemical_list: D004967:Estrogens; D004958:Estradiol
keywords: ACI rat; Brown Norway rat; breast cancer; estradiol; quantitative trait locus