The investigators have recently demonstrated that ovary-intact, but not ovariectomized, female ACI rates treated continually with near physiologic levels of the naturally occurring estrogen, 17b-estradiol (ES2), rapidly develop multiple and often invasive mammary carcinomas. More recently, they have examined induction by E2 of mammary carcinoma in F1, F2 and backcross (BC) progeny of a genetic cross between females of t he highly susceptible ACI inbred strain and males of a resistant inbred strain, Copenhagen (COP). The data from this experiment closely fit models in which susceptibility to E2 -induced mammary cancers is conferred by the dominantly acting ACI allele of a single gene, referred to as EMCA-1 (Estrogen-induced Mammary Cancer-1) Moreover, it appears that the dominantly acting COP allele of an independently segregating gene, referred to as MCS-X (Mammary cancer suppressor-X), may act to delay development of mammary carcinomas in E2 treated progeny. These data provide the first evidence that susceptibility to E2 -induced mammary cancers in any species behaves as a relatively simple Mendelian trait conferred and/or modulated through the actions of limited number of genes. Because of the well documented role of estrogens in etiology of breast cancer in humans, the ACI rat appears to represent a unique and highly relevant animal model for the study of this disease. The hypotheses underlying the research proposed herein are: 1)EMCA-1 is necessary and sufficient to confer susceptibility to E2-induced mammary cancers; and, 2. MCS-X, segregating independently from EMCA-1 suppresses susceptibility to these E2 -induced mammary cancers. Herein they propose to map within the rat genome the locations at which EMCA-1 and MCS-X reside, and confirm the roles of these putative genes as modulators of susceptibility to E2- induced mammary cancers. j They will also define the role of progesterone in the etiology of E2-induced mammary cancer development in the ACI rat strain and further validate this strain as an important animal model for the study of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA077876-01
Application #
2630789
Study Section
Special Emphasis Panel (ZRG2-PTHB (01))
Program Officer
Marks, Cheryl L
Project Start
1998-04-01
Project End
2003-01-31
Budget Start
1998-04-01
Budget End
1999-01-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Dennison, Kirsten L; Chack, Aaron C; Hickman, Maureen Peters et al. (2018) Ept7, a quantitative trait locus that controls estrogen-induced pituitary lactotroph hyperplasia in rat, is orthologous to a locus in humans that has been associated with numerous cancer types and common diseases. PLoS One 13:e0204727
Das Gupta, Soumyasri; Sae-tan, Sudathip; Wahler, Joseph et al. (2015) Dietary ?-Tocopherol-Rich Mixture Inhibits Estrogen-Induced Mammary Tumorigenesis by Modulating Estrogen Metabolism, Antioxidant Response, and PPAR?. Cancer Prev Res (Phila) 8:807-16
Samanas, Nyssa Becker; Commers, Tessa W; Dennison, Kirsten L et al. (2015) Genetic etiology of renal agenesis: fine mapping of Renag1 and identification of Kit as the candidate functional gene. PLoS One 10:e0118147
Dennison, Kirsten L; Samanas, Nyssa Becker; Harenda, Quincy Eckert et al. (2015) Development and characterization of a novel rat model of estrogen-induced mammary cancer. Endocr Relat Cancer 22:239-48
Flister, Michael J; Endres, Bradley T; Rudemiller, Nathan et al. (2014) CXM: a new tool for mapping breast cancer risk in the tumor microenvironment. Cancer Res 74:6419-29
Kurz, Scott G; Dennison, Kirsten L; Samanas, Nyssa Becker et al. (2014) Ept7 influences estrogen action in the pituitary gland and body weight of rats. Mamm Genome 25:244-52
Colletti 2nd, John A; Leland-Wavrin, Kristin M; Kurz, Scott G et al. (2014) 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. G3 (Bethesda) 4:1385-94
van Heesch, Sebastiaan; Mokry, Michal; Boskova, Veronika et al. (2013) Systematic biases in DNA copy number originate from isolation procedures. Genome Biol 14:R33

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