CD44 and Hyaluronan in the Regulation of Mammary Gland Development and Breast Cancer Progression

Abstract

Metastasis is the leading cause of death in patients with cancer, and the extracellular matrix is critical to cancer dissemination. The adhesion receptor, CD44, mediates cellular communication with the extracellular matrix by binding to the glycosaminoglycan, hyaluronan (HA). CD44 and HA play critical roles in cancer progression and development. HA is deposited in extracellular and pericellular matrices where it directs intracellular signaling through interactions with cell-surface CD44. CD44-HA interactions, in turn, direct signaling that is relevant to cancer progression. Importantly, these molecules can both promote and inhibit the oncogenic cascade, although the mechanism by which they promote dual and contrasting functions is unknown.Here we show that HA can both activate and suppress EGFR, a critical regulator of oncogenic signaling, in a context-dependent fashion. Using a 3D collagen system in which HA is either polymerized in collagen matrix or provided soluble in the media (sHA) we report that collagen-embedded HA (eHA) inhibits EGFR activation, filopodia formation, and cell spreading on a collagen matrix. Additionally, we show that CD44 is subject to cell-type changes during cancer progression. We have found that CD44 is expressed in the myoepithelium of the developing mammary gland and regulates the normal function of this cell type. The myoepithelial function of CD44 is also relevant to its role in cancer progression as CD44 is expressed in the basal cells of early-stage breast and prostate cancer but undergoes a basal to luminal epithelial switch with increasing tumorigenicity and is strongly expressed by tumor epithelium. These findings demonstrate a novel role for eHA as a protective molecule when encountered in the collagen matrix during cancer progression and highlight the importance of understanding cell-type specific contributions during cancer progression. Taken together, the findings reported in this dissertation point to a mechanism by which CD44 and HA can function in tumor suppression and promotion, depending on cell-type specific expression and modulation of the extracellular matrix.