We propose to determine what clinical characteristics, histologic features and molecular and genetic profiles are associated with elevated breast density and with increased risk of invasive breast cancer. Three large, well characterized study cohorts will be used to develop and test this model: (1) 600 women that have undergone mammography and breast biopsies with a benign diagnosis from 2006-9 at the University of California, San Francisco (UCSF) or California Pacific Breast Health Center (CPMC) in San Francisco;(2) 1500 women selected from a cohort of women with benign breast disease (BBD) from 1967- 1992 at the Mayo Clinic whose tissue has been collected and follow-up conducted to determine cancer status, and (3) 400 women that will have undergone screening mammography between 2006-7 at the UCSF Mt. Zion Breast Health Center. We will determine the following: (1) if histologic features (percentage fat, collagen, and epithelium) and a defined set of molecular and genetic characteristics associated with increased mammographic or compositional breast density and breast cancer risk identified in Project 2 [remodelled collagen, insulin-like growth factor binding proteins, cyclooxygenase (COX-2) are associated with extent of breast density measured as mammographic density, volumetric breast density, and compositional density among women with BBD, (2) if clinical characteristics, histologic features (percentage fat, collagen, and epithelium) and molecular and genetic characteristics of benign breast tissue correlated with increased breast density in Specific Aim #1 predict risk of breast cancer, type of invasive breast cancer (ER+ versus ER-), or time to development of cancer, and (3) if women with the 6A allele of TGFBR1 have increased breast density and those homozygous for the P(10) allele of TGF-b1 have decreased breast density and whether haplotypes at the TGF-b1 locus affect the extent of breast density. The results of these studies will provide information on what histologic characteristic and molecular and genetic profile contribute to increased breast density and risk of breast cancer, which may allow identification of a more precise measure of breast cancer risk.
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