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Date of Award

Summer 8-15-2015

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

High levels of fibrillar collagen in mammary tissue are correlated with increased incidence of breast tumor development in both mice and humans, and tumors that develop in this setting are more invasive and metastatic. Many invasive human breast cancers are associated with increased local collagen deposition (desmoplasia) and display increased perpendicular alignment of collagen fibers, both of which have been shown to be negative prognostic factors. We recently identified the collagen I receptor discoidin domain receptor 2 (DDR2) as a novel upstream regulator of Snail1 protein stability. Snail1 is a zinc finger transcriptional repressor that is considered to be a master regulator of the epithelial mesenchymal transition, which contributes to breast cancer metastasis by promoting tumor cell invasion and migration. These findings led us to hypothesize that DDR2 is necessary for metastasis in mouse models of breast cancer. We have demonstrated that DDR2 is required for breast cancer cell invasion and migration in vitro and for metastasis in vivo using a 4T1 orthotopic allograft model. To determine the cellular basis for the role of DDR2 in breast cancer metastasis in vivo, we generated a conditional allele of DDR2 and crossed it to the well-characterized MMTV-PyMT transgenic mouse model of breast cancer. A lacZ reporter contained within the targeted allele was used to show that DDR2 is expressed in MMTV-PyMT tumors at multiple stages of development, but not in normal mammary epithelium. Ubiquitous DDR2 deletion significantly inhibited lung metastasis in MMTV-PyMT mice, but did not affect primary mammary tumor growth or latency. DDR2 deletion in all mammary epithelial cells using K14-Cre inhibited lung metastasis, but DDR2 deletion specifically in the luminal mammary epithelial cells using MMTV-Cre only modestly reduced lung metastasis in MMTV-PyMT mice. This suggests a role for DDR2 in basal K14+ epithelial cells in primary breast tumors, which are known to be important for invasive leader cell properties during collective invasion/migration. In tumor stromal cells, the action of DDR2, likely in cancer-associated fibroblasts (CAFs), is critical for fibrillar collagen and extracellular matrix (ECM) production and the organization and architecture of collagen fibers. It also affects the tumor angiogenic response. The action of DDR2 modulates communication between breast tumor cells and their environment that facilitate breast cancer metastasis. This work identifies DDR2, a unique receptor tyrosine kinase, as a potential therapeutic target active in both tumor cells and tumor stromal cells of the tumor environment.

Language

English (en)

Chair and Committee

Gregory D Longmore

Committee Members

Sheila Stewart, Kendall Blumer, Jason Weber, Robert Mecham, Jeffrey Miner

Comments

Permanent URL: https://doi.org/10.7936/K73J3B73

Available for download on Thursday, August 15, 2115

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