Grant Number:	5R01CA050468-20 Interpret this number
Primary Investigator:	Dupont, William
Organization:	Vanderbilt University
Project Title:	Epidemiology of Molecular Risk Factors for Breast Cancer
Fiscal Year:	2011

DESCRIPTION (provided by applicant): 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.




Interdependence Of Radial Scar And Proliferative Disease With Respect To Invasive Breast Carcinoma Risk In Patients With Benign Breast Biopsies
Authors: Sanders M.E. , Page D.L. , Simpson J.F. , Schuyler P.A. , Dale Plummer W. , Dupont W.D. .
Source: Cancer, 2006-04-01 00:00:00.0; 106(7), p. 1453-61.
PMID: 16502407
Related Citations

The Natural History Of Low-grade Ductal Carcinoma In Situ Of The Breast In Women Treated By Biopsy Only Revealed Over 30 Years Of Long-term Follow-up
Authors: Sanders M.E. , Schuyler P.A. , Dupont W.D. , Page D.L. .
Source: Cancer, 2005-06-15 00:00:00.0; 103(12), p. 2481-4.
PMID: 15884091
Related Citations

Transforming Growth Factor-beta And Breast Cancer Risk In Women With Mammary Epithelial Hyperplasia
Authors: Gobbi H. , Dupont W.D. , Simpson J.F. , Plummer W.D. , Schuyler P.A. , Olson S.J. , Arteaga C.L. , Page D.L. .
Source: Journal Of The National Cancer Institute, 1999-12-15 00:00:00.0; 91(24), p. 2096-101.
PMID: 10601380
Related Citations

Power And Sample Size Calculations For Studies Involving Linear Regression
Authors: Dupont W.D. , Plummer W.D. .
Source: Controlled Clinical Trials, 1998 Dec; 19(6), p. 589-601.
PMID: 9875838
Related Citations

Association Of Cytochrome P450 1b1 (cyp1b1) Polymorphism With Steroid Receptor Status In Breast Cancer
Authors: Bailey L.R. , Roodi N. , Dupont W.D. , Parl F.F. .
Source: Cancer Research, 1998-11-15 00:00:00.0; 58(22), p. 5038-41.
PMID: 9823305
Related Citations

Monoclonality In Fibroadenomas With Complex Histology And Phyllodal Features
Authors: Kasami M. , Vnencak-Jones C.L. , Manning S. , Dupont W.D. , Jensen R.A. , Page D.L. .
Source: Breast Cancer Research And Treatment, 1998 Jul; 50(2), p. 185-91.
PMID: 9822223
Related Citations

Breast Cancer And Cypia1, Gstm1, And Gstt1 Polymorphisms: Evidence Of A Lack Of Association In Caucasians And African Americans
Authors: Bailey L.R. , Roodi N. , Verrier C.S. , Yee C.J. , Dupont W.D. , Parl F.F. .
Source: Cancer Research, 1998-01-01 00:00:00.0; 58(1), p. 65-70.
PMID: 9426059
Related Citations

Loss Of Heterozygosity And Microsatellite Instability In Breast Hyperplasia. No Obligate Correlation Of These Genetic Alterations With Subsequent Malignancy
Authors: Kasami M. , Vnencak-Jones C.L. , Manning S. , Dupont W.D. , Page D.L. .
Source: The American Journal Of Pathology, 1997 Jun; 150(6), p. 1925-32.
PMID: 9176386
Related Citations

Expression Of Most Matrix Metalloproteinase Family Members In Breast Cancer Represents A Tumor-induced Host Response
Authors: Heppner K.J. , Matrisian L.M. , Jensen R.A. , Rodgers W.H. .
Source: The American Journal Of Pathology, 1996 Jul; 149(1), p. 273-82.
PMID: 8686751
Related Citations

Continued Local Recurrence Of Carcinoma 15-25 Years After A Diagnosis Of Low Grade Ductal Carcinoma In Situ Of The Breast Treated Only By Biopsy
Authors: Page D.L. , Dupont W.D. , Rogers L.W. , Jensen R.A. , Schuyler P.A. .
Source: Cancer, 1995-10-01 00:00:00.0; 76(7), p. 1197-200.
PMID: 8630897
Related Citations

P53 Mutations Are Confined To The Comedo Type Ductal Carcinoma In Situ Of The Breast. Immunohistochemical And Sequencing Data
Authors: O'Malley F.P. , Vnencak-Jones C.L. , Dupont W.D. , Parl F. , Manning S. , Page D.L. .
Source: Laboratory Investigation; A Journal Of Technical Methods And Pathology, 1994 Jul; 71(1), p. 67-72.
PMID: 8041120
Related Citations

P53 Gene Mutations And Steroid Receptor Status In Breast Cancer. Clinicopathologic Correlations And Prognostic Assessment
Authors: Caleffi M. , Teague M.W. , Jensen R.A. , Vnencak-Jones C.L. , Dupont W.D. , Parl F.F. .
Source: Cancer, 1994-04-15 00:00:00.0; 73(8), p. 2147-56.
PMID: 8156519
Related Citations

Ductal Carcinoma In Situ Of The Breast. Heterogeneity Of Individual Lesions
Authors: Lennington W.J. , Jensen R.A. , Dalton L.W. , Page D.L. .
Source: Cancer, 1994-01-01 00:00:00.0; 73(1), p. 118-24.
PMID: 8275415
Related Citations

Anatomic Indicators (histologic And Cytologic) Of Increased Breast Cancer Risk
Authors: Page D.L. , Dupont W.D. .
Source: Breast Cancer Research And Treatment, 1993 Nov; 28(2), p. 157-66.
PMID: 8173068
Related Citations

Breast Cancer Risk Associated With Proliferative Breast Disease And Atypical Hyperplasia
Authors: Dupont W.D. , Parl F.F. , Hartmann W.H. , Brinton L.A. , Winfield A.C. , Worrell J.A. , Schuyler P.A. , Plummer W.D. .
Source: Cancer, 1993-02-15 00:00:00.0; 71(4), p. 1258-65.
PMID: 8435803
Related Citations

Menopausal Estrogen Replacement Therapy And Breast Cancer
Authors: Dupont W.D. , Page D.L. .
Source: Archives Of Internal Medicine, 1991 Jan; 151(1), p. 67-72.
PMID: 1824675
Related Citations