Abstract
Breast cancer is the leading cause of cancer-related mortalities amongst women worldwide. Due to the incomplete understanding of the complex mechanisms that lead to and drive metastasis, effective therapeutic options in late-stage metastatic disease are very limited.
The Receptor ffor Advanced Glycation End-products (RAGE) has been implicated to play a significant role in multiple stages of breast cancer pathophysiology. RAGE-ligand signaling has been linked to increased malignancy, invasiveness and risk of metastasis. RAGE-ligand signaling impacts both tumor cell-intrinsic and tumor cell-extrinsic mechanisms. Although, these links have been demonstrated in some some in vitro and in vivo models and human tumor tissues, the complex mechanisms by which RAGE contributes to tumor progression and metastasis are still not well-defined.
In this thesis work, I tested the anti-metastatic effect of two small molecule RAGE inhibitors in a preclinical model of triple-negative metastatic breast cancer, and analyzed drug mechanism of action on the primary and metastasized tumor cells. To enable genetic studies of RAGE in syngeneic metastatic BC models, I performed detailed characterization of three C57Bl6 syngeneic mouse models. And finally, I tested the PY8119 syngeneic model for RAGE-driven host effects using RAGE knockout mice, which revealed that RAGE signaling in the host alters immune response, and tumor growth.
In conclusion, these data together demonstrate that RAGE plays critical roles in both the tumor cells and tumor stroma, and together drives metastasis of BC. Therapeutic targeting of RAGE with clinically relevant small molecular inhibitors impaired metastatic cancer, and underscores the translation of RAGE inhibitors to human clinical trials.