In humans, a common risk factor for the development of invasive breast cancer is dense breast tissue, detected by mammography. This dense tissue is associated with increased stromal collagen, increased epithelial cells, and decreased fatty tissue. Recent studies in transgenic mice indicate that increased collagen density in breast stromal tissue plays a causative role in promoting both the formation and invasiveness of breast tumors. Additional studies implicate tissue rigidity downstream of extracellular matrix (ECM) deposition and/or cross linking in promoting aggressive, invasive cellular phenotypes. Conversely, basement membrane ECM proteins that underlie normal and carcinoma in situ epithelial cells are thought to inhibit tumor progression. Because of the complexity of extracellular matrix-tumor cell interactions, it is difficult to fully isolate and understand the various effects of extracellular matrix on tumor progression using traditional biological approaches. We therefore propose to use an interdisciplinary approach in which we develop a 3-dimensional cell-based multiscale mathematical model of ECM-breast cancer interactions. Using this model, we will perform in silico experiments to test the overall hypothesis that ECM rigidity and stromal collagen fibrosis provide an environment that promotes tumor progression and invasion. We will specifically test the role of collagen fibril density, width, alignment, and crosslinking and the role of basement membrane ECM and proteases on cancer growth and invasion. All modeling will be fully integrated with experimentation to obtain realistic parameters and separately test predictions. We anticipate that this project will identify critical microenvironmental factors promoting breast cancer progression and lay the groundwork for future therapeutic intervention.

Public Health Relevance

This project will combine mathematical modeling and experimental approaches to study the role of extracellular matrix on breast cancer progression and invasion. The project is relevant to human health because it will lead to a mechanistic understanding ofthe tissue and cellular factors that underlie dense breast tissue as a risk factor for invasive breast cancer and potentially identify novel therapeutic avenues.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA143069-02
Application #
8231321
Study Section
Special Emphasis Panel (ZCA1-SRLB-C (O1))
Program Officer
Couch, Jennifer A
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$461,853
Indirect Cost
$99,475
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Lee, Byoungkoo; Zhou, Xin; Riching, Kristin et al. (2014) A three-dimensional computational model of collagen network mechanics. PLoS One 9:e111896
Weaver, Alissa M; Page, Jonathan M; Guelcher, Scott A et al. (2013) Synthetic and tissue-derived models for studying rigidity effects on invadopodia activity. Methods Mol Biol 1046:171-89
Hoshino, Daisuke; Branch, Kevin M; Weaver, Alissa M (2013) Signaling inputs to invadopodia and podosomes. J Cell Sci 126:2979-89