A DUAL ROLE OF INTEGRIN ALPHA-3 IN BREAST CANCER CNS METASTASIS & CHEMORESISTANCE

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ABSTRACT Integrins serve a multifaceted role in cancer progression by regulating cell migration as well as mediating signaling pathways important in proliferation and chemoresistance. Our lab was the first to demonstrate that leukemia cells use a neural stem cell migratory pathway to invade the central nervous system (CNS) by migrating along the abluminal surface of blood vessels that traverse the bone marrow and leptomeninges (LM). We showed that this process was mediated by leukemia cell integrin α6 engaging laminin in the basement membrane surrounding these vessels. Similar to leukemia, breast cancer metastasis to the LM results in severe morbidity and is a rapidly fatal complication. My preliminary data suggest that breast cancer cells utilize both α6 and α3 integrin-laminin interactions to invade the LM. I have also observed that breast cancer cells plated on laminin exhibit resistance to the chemotherapeutic doxorubicin. Integrin α6 KO does not sensitize the cells to chemotherapy leading me to hypothesize that integrin α3 serves a multifaceted role by activating chemoprotective signaling pathways upon laminin engagement. In this research grant, I propose to more fully define the role of α3 integrin-laminin interactions in regulating triple negative breast cancer LM metastasis along emissary vessels and in promoting chemoresistance in the metastatic microenvironment.