We propose to determine what clinical characteristics, histologic features and molecular and genetic profilesare 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 womenthat have undergone mammography and breast biopsies with a benign diagnosis from 2006-9 at theUniversity of California, San Francisco (UCSF) or California Pacific Breast Health Center (CPMC) in SanFrancisco; (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 cancerstatus, and (3) 400 women that will have undergone screening mammography between 2006-7 at the UCSFMt. Zion Breast Health Center.We will determine the following: (1) if histologic features (percentage fat, collagen, and epithelium) and adefined set of molecular and genetic characteristics associated with increased mammographic orcompositional breast density and breast cancer risk identified in Project 2 [remodelled collagen, insulin-likegrowth factor binding proteins, cyclooxygenase (COX-2) are associated with extent of breast densitymeasured as mammographic density, volumetric breast density, and compositional density among womenwith BBD, (2) if clinical characteristics, histologic features (percentage fat, collagen, and epithelium) andmolecular and genetic characteristics of benign breast tissue correlated with increased breast density inSpecific Aim #1 predict risk of breast cancer, type of invasive breast cancer (ER+ versus ER-), or time todevelopment of cancer, and (3) if women with the 6A allele of TGFBR1 have increased breast density andthose homozygous for the P(10) allele of TGF-b1 have decreased breast density and whether haplotypes at theTGF-b1 locus affect the extent of breast density.The results of these studies will provide information on what histologic characteristic and molecular andgenetic profile contribute to increased breast density and risk of breast cancer, which may allowidentification of a more precise measure of breast cancer risk.
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