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

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.
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