The ultimate goal of this research is to define the mechanisms through which specific endocrine and genetic risk factors contribute to breast cancer development. The focus of this proposed study is Emca4, a genetic determinant of susceptibility to 17?-estradiol (E2)-induced mammary cancer in the rat that has been mapped to rat chromosome 7 (RNO7). Data presented herein indicate that Emca4 harbors multiple genetic determinants of mammary cancer susceptibility that are orthologous to breast cancer risk loci mapped to chromosome 8q24.21. Also presented are novel data that indicate that a risk prediction model based on genotype across the Emca4 orthologous regions in the human genome can accurately distinguish cases from controls in a previously characterized case/control cohort. The primary objectives of this proposed study are to identify the cell types in which and the mechanisms through which the Emca4 variants influence development of mammary cancer. The knowledge gained will be translate to studies of human derived biospecimens to assess relevance of the data emerging from the rat models.
Aim 1 is to define the mechanisms through which Emca4.1 determines susceptibility to E2-induced mammary cancer. The genes upon which the Emca4.1 variants act will be identified in defined mammary cell populations.
Aim 2 is to define the mechanism through which Emca4.4 influences mammary cancer susceptibility and modifies the actions of Emca4.1. The molecular bases of the epistatic interactions between Emca4.4 and Emca4.1 on mammary cancer susceptibility and the cellular and molecular phenotypes regulated by Emca4.4 and Emca4.1 will be defined.
Specific Aim 3 is to define the function(s) of Pvt1 in the rat mammary gland and its role in mammary cancer development. Attention will be focused on functionally characterizing Pvt1 promoters and exons that are impacted by endocrine and genetic factors or differ between matched normal and neoplastic mammary/breast tissues. Novel, physiologically relevant, rat models of E2-induced mammary cancer will be utilized in this research. Successful completion of the proposed studies proposed is expected to identify the cell types in which the actions of the Emca4 variants on mammary cancer susceptibility are exerted, the specific gene product(s) that confers the actions of the Emca4 variants in those cell types, and the downstream biological processes that are influenced by the functional orthologs that reside within Emca4. The information generated in these studies is expected to advance our understanding of the etiology of the luminal breast cancer subtypes.

Public Health Relevance

to public health: This proposed research utilizes novel and physiologically relevant rat models of 17?-estradiol (E2)-induced mammary cancer to define the mechanisms and sites of action of ?functional orthologs? that reside within the Emca4 mammary cancer susceptibility locus in rat and the genetically orthologous 8q24 breast cancer risk locus in humans. By genetically linking the Emca4/8q24 functional orthologs to the biological processes that influence development of E2-induced mammary cancer, these studies will enhance our knowledge of how genetic and endocrine factors interact to influence normal mammary gland biology and mammary cancer susceptibility and will lay the foundation for development of novel strategies for breast cancer risk prediction and prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA204320-03
Application #
9637239
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Fingerman, Ian M
Project Start
2017-03-01
Project End
2022-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Shull, James D; Dennison, Kirsten L; Chack, Aaron C et al. (2018) Rat models of 17?-estradiol-induced mammary cancer reveal novel insights into breast cancer etiology and prevention. Physiol Genomics 50:215-234
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
Jerry, D Joseph; Shull, James D; Hadsell, Darryl L et al. (2018) Genetic variation in sensitivity to estrogens and breast cancer risk. Mamm Genome 29:24-37