Role of CD44 and its main ligand, hyaluronan, in breast cancer invasion

Breast cancer is the second most frequent cancer in middle-aged women. Control of this disease requires identification of the various factors involved in the invasive-metastatic cascade, facilitating the subsequent development of relevant blocking compounds.Tumor cell invasion is a complex sequence of events where cell adhesion molecules exert determinant roles. CD44 is a family of cell adhesion glycoproteins generated by alternative splicing of up to ten variant exons. Discrete CD44 isoforms are overexpressed in different human cancers, including breast cancer. CD44 is expressed on the plasma membrane of cells and binds mainly to hyaluronan. Hyaluronan is a negatively charged high-molecular-weight glycosaminoglycan conspicuously present in the extracellular matrix ant its concentration is increased at sites of tissue remodeling.This study tested the hypothesis that CD44 and its main ligand, hyaluronan participate in the invasive properties of breast cancer cells. The hypothesis is based on the following rationale: the previously documented upregulation of CD44 expression in human breast cancer tumors, the role of CD44 in the invasive properties of nonepithelial cells in vitro, and the high concentrations of hyaluronan present in human breast cancer tumors.The experiments were performed with different human breast cancer cell lines. In one cell line, CD44 and its v6 variant isoform participate directly in tumor cell invasion in vitro. Moreover, hyaluronan alters cell behavior in vitro, mainly by changing CD44 expression, adhesion and motility of breast cancer cells with high CD44 expression. In addition, it is shown that intratumoral injection of hyaluronan reduces the volume of tumors produced by orthotopically xenotransplanted breast cancer cells.The contribution of these studies to the advance of knowledge in breast cancer is based on a role of CD44 and hyaluronan in the interactions between tumor cells and the extracellular matrix, offering an opportunity to develop a new therapeutic strategy