We propose to study molecular, genetic and histologic markers of breast cancer risk in women with benign breast disease. We will use a unique cohort of such women to pursue the following Specific Aims: 1. To determine the effects on breast cancer risk of the 6A polymorphism of the transforming growth factor beta type I receptor (T(3R-I). We will also study how expression levels of the TpR-l, and its principal substrate Smad2, affect breast cancer risk in women with proliferative breast lesions. 2. To evaluate the combined influence on breast cancer risk of benign breast lesions and 424 single nucleotide polymorphisms (SNPs) from 86 candidate genes involved in estrogen biosynthesis, function and oxidative metabolism. Cross-sectional analyses will also be performed that examine how specific genotypes are correlated with different types of benign breast disease. These studies will explore potential influences on breast cancer risk of ER-mediated cell proliferation or the generation of oxidative estrogen metabolites that may damage DNA. 3. To expand the size and length of follow-up of our study cohort. The research will be based on a large retrospective cohort study of women who underwent benign breast biopsy between 1954 and 1995. Paraffin-embedded tissue from the entry biopsy of these patients is available. By the end of this project we estimate that we will have observed 890 breast cancer cases during follow-up among the 11,547 members of this cohort. We will conduct a series of nested case- control studies on these women. The 890 breast cancer cases will be matched by race, age and year of their benign breast biopsy to 1780 controls (1:2 ratio). Genotyping will be performed using the Illumina GoldenGate assay while immunohistochemical methods will be used to identify abnormal protein expression. We will use supervised principal component analyses to assess the individual and combined effects of molecular, histologic and epidemiologic variables on breast cancer risk. A false discovery rate (FDR) approach will be used to identify promising findings that will be subject to validation in other data sets. This project takes advantage of an established cohort of women with biopsy-confirmed benign breast disease. Clinical, demographic, and histologic information, as well as genomic DNA is uniformly available. This project will permit the combination of modern methods in molecular biology, genetics, pathology and epidemiology to assess potentially powerful new markers of breast cancer progression and prognosis. We expect that it will lead to important advances in the prevention and treatment of this disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Lam, Tram K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Biostatistics & Other Math Sci
Schools of Medicine
United States
Zip Code
Parl, Fritz F; Crooke, Philip S; Plummer Jr, W Dale et al. (2018) Genomic-Epidemiologic Evidence That Estrogens Promote Breast Cancer Development. Cancer Epidemiol Biomarkers Prev 27:899-907
Degnim, Amy C; Visscher, Daniel W; Radisky, Derek C et al. (2016) Breast cancer risk by the extent and type of atypical hyperplasia. Cancer 122:3087-8
Degnim, Amy C; Dupont, William D; Radisky, Derek C et al. (2016) Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women. Cancer 122:2971-8
Hartmann, Lynn C; Degnim, Amy C; Santen, Richard J et al. (2015) Atypical hyperplasia of the breast--risk assessment and management options. N Engl J Med 372:78-89
Sanders, Melinda E; Schuyler, Peggy A; Simpson, Jean F et al. (2015) Continued observation of the natural history of low-grade ductal carcinoma in situ reaffirms proclivity for local recurrence even after more than 30 years of follow-up. Mod Pathol 28:662-9
Higginbotham, Kathryn S; Breyer, Joan P; McReynolds, Kate M et al. (2012) A multistage genetic association study identifies breast cancer risk loci at 10q25 and 16q24. Cancer Epidemiol Biomarkers Prev 21:1565-73
Boulos, Fouad I; Dupont, William D; Schuyler, Peggy A et al. (2012) Clinicopathologic characteristics of carcinomas that develop after a biopsy containing columnar cell lesions: evidence against a precursor role. Cancer 118:2372-7
Crooke, Philip S; Justenhoven, Christina; Brauch, Hiltrud et al. (2011) Estrogen metabolism and exposure in a genotypic-phenotypic model for breast cancer risk prediction. Cancer Epidemiol Biomarkers Prev 20:1502-15
Higginbotham, Kathryn S P; Breyer, Joan P; Bradley, Kevin M et al. (2011) A multistage association study identifies a breast cancer genetic locus at NCOA7. Cancer Res 71:3881-8
Dupont, William D; Breyer, Joan P; Bradley, Kevin M et al. (2010) Protein phosphatase 2A subunit gene haplotypes and proliferative breast disease modify breast cancer risk. Cancer 116:8-19

Showing the most recent 10 out of 42 publications