6th International Workshop on Breast Densitometry and Breast ...

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6 th <strong>International</strong> <strong>Workshop</strong> on Breast Densitometry and Breast Cancer Risk Assessment COLLAGEN ALIGNMENT SURROUNDING BREAST TUMORS FACILITATES TUMOR SPREAD AND METASTASIS Suzanne M. Ponik 1 , Kristin M. Riching 1 , Kevin W. Eliceiri 1 , Paolo P. Provenzano 2 , Patricia J. Keely 1 ABSTRACTS FOR SPEAKERS 1 Laboratory for Cellular and Molecular Biology and UW Carbone Cancer Center, University of Wisconsin, Madison, 53706; 2 Department of Biomedical Engineering and UMCCC, University of Minnesota, Minneapolis, 55455 While mammographic density has been correlated to increased risk of breast cancer in several studies, relatively little is known regarding the mechanisms by which mammographic density contributes to risk. Using mouse models of increased collagen in the connective tissue stroma, we find a causal link between increased stromal collagen and increased formation of mammary tumors. Tumors that arise in dense collagen are more invasive and demonstrate dramatic changes in gene expression compared to tumors that arise in non-dense mammary tissue. At the structural level, we find that mammary tissue has non-aligned, curly collagen fibers that are altered during tumor progression. These changes, termed Tumor Associated Collagen Signatures (TACS) manifest as a consistent progression from increased unaligned collagen (TACS-1), to straight collagen fibers (TACS-2) to straight collagen fibers aligned perpendicular to the tumor/stromal boundary (TACS-3). Mechanistically, TACS-3 collagen provides a “highway” on which tumor cells are able to migrate out from the tumor and invade into distal sites. TACS-3 signatures correlate to increased metastases in mouse models. In mouse models, similar rearrangements of collagen are also observed at the sites of lung metastasis, suggesting the collagen rearrangements facilitate not only spread, but also survival in metastatic sites. Importantly, collagen structural changes are also found in human breast cancer: analysis of 203 archived samples from patients with invasive breast cancer demonstrates that the presence of TACS-3 collagen significantly predicts increased relapse. Thus, TACS-3 collagen represents a potential biomarker. Current work is investigating ways that collagen changes can be targeted to better treat breast cancer in women with dense breast tissue. 16
6 th <strong>International</strong> <strong>Workshop</strong> on Breast Densitometry and Breast Cancer Risk Assessment GENETIC MARKERS OF BREAST DENSITY-ETHNIC ASSOCIATION TO BREAST DENSITY Elad Ziv, MD Department of Medicine, University of California San Francisco Introduction: Percent mammographic density (PMD) adjusted for age and BMI is one of the strongest risk factors for breast cancer and is known to be approximately 60 percent heritable. Here we report a finding of an association between genetic ancestry and adjusted PMD. Methods: We selected self-identified Caucasian women in the California Pacific Medical Center Research Institute Cohort whose screening mammograms placed them in the top or bottom quintiles of age- and body mass index-adjusted PMD. Our final data set included 474 women with the highest adjusted PMD and 469 with the lowest genotyped on the Illumina 1M platform. Principal component analysis (PCA) and identity-by-descent (IBD) analyses allowed us to infer the women's genetic ancestry and correlate it with adjusted PMD. Results: Women of Ashkenazi Jewish ancestry, as defined by the first principal component (PC1) of PCA and identity-by-descent analyses, represented approximately 15 percent of the sample. Ashkenazi Jewish ancestry, defined by PC1, was associated with higher adjusted PMD (p = 0.004). Using multivariate regression to adjust for epidemiologic factors associated with PMD, including age at parity and use of postmenopausal hormone therapy, did not attenuate the association. Conclusion: Women of Ashkenazi Jewish ancestry based on genetic analysis are more likely to have high age- and BMI-adjusted PMD. Ashkenazi Jews may have a unique set of genetic variants or environmental risk factors that increase mammographic density. ABSTRACTS FOR SPEAKERS 17
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