Normal breast epithelial growth and differentiation is under the control of two well-studied molecularsignaling pathways mediated by the epithelial growth factor (ERBB) and transforming growth factor(TGF- .) receptor families. These pathways are also closely intertwined in the etiology of benignproliferative breast disease and breast cancer. The overall objective of this study is to identifypredictors of breast cancer by investigating how genetic variation within the well-defined interactingERBB and TGF- signaling pathways interact with histologically defined breast lesions to affect breastcancer risk. We approach this objective by comprehensively studying a unique cohort of 7,923women who underwent biopsy for benign breast disease, 529 of whom have developed invasive breastcancer or ductal carcinoma in situ during follow-up. The cohort is accompanied by epidemiologicaldata of established breast cancer risk factors, paraffin-embedded tissue blocks of the initial benignbreast disease biopsy, and rigorous pathologic detail of both the initial biopsy and subsequent tumor.We will conduct nested case-control studies on these patients. We also seek to perform an accuratewhole genome amplification, which will provide an inexhaustible resource for investigating interactionsbetween benign histology and other genetic traits. This cohort is being expanded through a separateR01 grant. We expect that over the next five years our nested case control study will expand to 890cases and 1780 controls.
Our specific aims are as follows:1. To determine how genes that control ERBB signaling interact with each other and with benignbreast disease to affect breast cancer risk.
This Aim will focus on genes central to the ERBBsignaling pathway. We will investigate the pathway in 600 cases and 1200 controls. We will applyLD mapping using efficient tagging SNPs to capture genetic diversity of each locus.2. To determine how polymorphisms in genes central to the TGF- signaling pathways interact witheach other and with benign breast disease to affect breast cancer risk. The approach will follow thatof Aim 1.3. To define all variants in full linkage disequilibrium and that directly mark each haplotypesignificantly associated with progression to breast cancer. The narrow subset of these geneticvariants, among all others at the gene, is a set of candidates that may be etiologically associatedwith breast cancer.
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