Secretory products of breast cancer cells upregulate hyaluronan production in a human osteoblast cell line

Hyaluronan (HA) has been implicated in breast cancer progression and metastasis to lymph nodes. Although breast cancer has a strong propensity for metastasis to the bone, the role of HA in the development of bone metastasis in breast cancer is not well delineated. In order to determine the role of HA in breast cancer induced osteolysis, we examined the effect of secretory products in the conditioned medium of breast cancer cell lines on the expression of hyaluronan synthases (HAS), accumulation of HA in pericellular matrix, secretion of HA in the culture media, and on expression of surface HA receptors, in a human immature osteoblast cell line (Hfob). Our results show that conditioned medium derived from breast cancer cells upregulate the expression of hyaluronan synthases, HAS1 and HAS2, followed by significant increase in pericellular and secreted HA in Hfob cells. Our results further demonstrate that both CD44 and receptor for hyaluronan-mediated motility (RHAMM) are involved in binding cell surface associated HA on Hfob cells. Analysis of the growth factors in the conditioned medium implicates TGF-beta 1 in the modulation of HAS1 and HAS2, as well as in the increase in pericellular and secreted HA. This report is the first to show that soluble factors produced by breast cancer cells mediate increase in HA production in osteoblasts.