REGULATION OF HYALURONAN TURNOVER IN THE DEVELOPING MAMMARY GLAND AND ITS CONTRIBUTION TO CD44 SIGNALING AND INFLAMMATION IN BREAST CANCER

Abstract

Cancer has been compared to a chronic wound unable to heal, as the balance is tipped in favor of pro-tumor inflammation. Therefore, it is important to understand how cancer cells interact with and alter their environment to ultimately support disease progression. Hyaluronan (HA) is of particular interest as it is a large glycosaminoglycan of the extracellular matrix that has anti-inflammatory effects under physiologic conditions. However, under conditions of organismal stress, an increase in HA deposition and fragmentation occurs, yet it is unknown how HA deposition impacts malignant progression. We begin by comparing HA machinery within murine mammary glands to aid in our understanding of its aberrant regulation in tumors. To our knowledge, we are the first to characterize HA deposition within the murine mammary gland across key stages of development. Additionally, our findings support a novel role for macrophages in homeostatic and aberrant HA turnover. Furthermore, we demonstrate that breast cancer cells promote cancer-associated inflammation through HA-CD44 interactions, and this axis contributes to early tumor formation. Importantly, our results are supported by data from human breast cancer cases, where increased hyaluronan synthase 2 expression significantly correlates with an inflammatory gene signature. Finally, we define a link between fibroblast growth factor receptor (FGFR)-mediated activation of HA synthesis and HA-CD44 driven macrophage recruitment during early tumorigenesis. Overall, this work establishes essential groundwork for future studies aiming to identify key targets and new therapeutic approaches for the treatment of breast cancer. Because high levels of HA deposition within many tumor types yields a poorer prognosis, our results emphasize that HA-CD44 interactions potentially have broad implications across multiple cancers.