Clinicopathological significance of hyaluronan and hyaluronidase 2 (HYAL2) in breast cancer.

Hyaluronan (HA), as a component of extracellular matrix, has pivotal roles in both physiological and pathological condition. In breast cancer, while high molecular weight HA is produced by hyaluronan synthase, it is degraded by hyaluronidases (hyaluronidase-1 (HYAL1) and hyaluronidase-2 (HYAL2)) into low molecular weight HA (LMW HA), which is considered to have pro-tumorigenic effects in human malignancies. However, HA and HYAL2, the rate-limiting enzyme of HA degradation, have not been comprehensively examined in breast cancer and clinicopathological significance of LMW HA remains to be elucidated in breast cancer. We therefore histochemically localized HA as well as HYAL2 in 116 breast cancer tissues. In addition, we examined size-dependent function of HA on breast cancer cell proliferation and migration using MCF-7 and MDA-MB-231 breast cancer cell lines. HA was localized in both the stroma and breast carcinoma cells, while HYAL2 was predominantly localized in breast carcinoma cells. HA was significantly correlated with cell proliferation and invasion ability as well as increased risk of recurrence especially in HYAL2 positive group. On the other hand, HYAL2 was correlated with breast cancer cell proliferation and increased risk of recurrence. In addition, in vitro analyses revealed that lower molecular weight HA increased sphere forming ability and migration in MCF-7 and MDA-MB-231, whereas higher molecular weight HA inhibited them. It was concluded that HA needs to be degraded by HYAL2 to exert pro-tumorigenic effects and comprehensive HA/HYAL2 status serves as a potent prognostic factor in breast cancer.