Publication Date

2017-04-26

Availability

Open access

Embargo Period

2017-04-26

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Molecular Cell and Developmental Biology (Medicine)

Date of Defense

2017-02-24

First Committee Member

Barry I. Hudson

Second Committee Member

Christian H. Faul

Third Committee Member

Thomas Emmanuel

Fourth Committee Member

Marc E. Lippman

Abstract

The Receptor for Advanced Glycation End-products (RAGE) is pattern recognition receptor for multiple ligands including AGEs, DNA, HMGB1, and various S100 proteins. Studies have shown that RAGE is involved in numerous pathologic states including Diabetes, Atherosclerosis, Alzheimer’s disease, and various cancers. RAGE expression and activation have been shown to be associated with various cancer models including breast cancer. However, little is known of the mechanistic role of RAGE signaling in breast cancer progression and metastasis, and the therapeutic potential of RAGE inhibition. We therefore hypothesized that RAGE-ligand signaling in both the tumor and tumor microenvironment drives breast cancer invasion and metastasis. In Specific Aim 1, we explored the in vitro signaling and functional effects of RAGE-ligand signaling in tumor cells. In Specific Aim 2, we dissected the in vivo role of RAGE in the tumor and tumor microenvironment using xenograft (NOD/SCID) and syngeneic mouse models (BALB/c and C57BL/6) of breast cancer. Finally, in Specific Aim 3, we tested the effects of RAGE inhibitors, (FPS-ZM1 and Oxyclozanide) on inhibition of breast cancer signaling and breast cancer progression and metastasis. In vitro, we found that metastatic human and mouse breast cancer cells show increased RAGE expression, and RAGE drives increased breast cancer cell invasiveness and migration activities through a MEK-dependent signaling pathway. In vivo, RAGE shRNA in MDA-MB-231 cells inhibits metastasis to liver in lung in xenograft models. Moreover, knockdown of RAGE from 4T-1 murine breast cancer mouse model showed less tumor growth and distant metastasis in in vivo syngeneic mouse. Interestingly, RAGE knockout mice (RAGE -/-) displayed striking impairment of tumor cell growth with AT-3 (MMTV-PyMT spontaneous breast cancer cell) compared to wildtype RAGE (+/+) mice. Finally, we showed for the first time that novel RAGE antagonists could powerfully suppress breast cancer cell invasiveness in vitro and metastasis in vivo. Taken together, these data provide evidence that RAGE contributes importantly to breast cancer progression and metastasis, through tumor intrinsic and tumor microenvironmental effects, and that targeting of RAGE may present a novel therapeutic approach in metastatic breast cancer.

Keywords

RAGE; Breast Cancer; Metastasis; EMT; S100

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