The expression of heparanase-1 (Hpa1) is elevated in virtually all major types of cancer, where it plays a key role in promoting tumor progression, inflammation and angiogenesis. As the only known protein in mammals capable of cleaving heparan sulfate, Hpa1 enzymatic activity can shorten the heparan sulfate chains attached to proteoglycans such as Syndecan-1, rendering the core protein increasingly susceptible to cleavage, which in turn leads to the shedding of the proteoglycan. Shed Syndecan-1 can act in paracrine fashion and promote tumor progression and metastasis.

Hence, in recent years, Hpa1 has become a prominent target for anticancer therapies. In contrast, heparanase-2 (Hpa2), a close homologue of Hpa1, has received little attention, due to its lack of enzymatic activity. However, Hpa2 is not an inert protein, as studies indicate that it exhibits a higher affinity towards heparin and heparan sulfate than Hpa1, thereby interfering with the interaction of Hpa1 with its substrate. Therefore, Hpa2 has been proposed to act as a tumor suppressor.

Part of our research focuses on elucidating the role of Hpa2 in breast cancer development, particularly its interaction with Hpa1 and SDC1. To investigate these interactions, we utilize breast cancer cell lines engineered to overexpress Hpa2. Through a series of experiments, we examine how Hpa2 influences key processes of tumor development such as Syndecan-1 shedding, cell invasion, angiogenesis, and cell proliferation.
 

This project is funded by the Deutsche Forschungs-Gesellschaft (DFG).