Heparanase Promotes Mammary Gland Branching Morphogenesis and Tumor Growth

Recently, we have shown that over expression of heparanase or its C-terminal domain (8C) that mediate signaling properties of heparanase, by human breast MCF10A cells results in larger and asymmetrical acinar-like structures. In order to explore the role of heparanase in mammary gland development we have targeted heparanase and 8C expression to the mammary gland of transgenic mice utilizing the regulatory elements of the mouse mammary tumor virus (MMTV). Specific targeting of heparanase or the 8C variant to the mammary epithelium at relatively low levels was sufficient to enhance mammary gland development evident by thicker end-buds and more branch alveolar structures that densely fill the mammary fat pad. Enhanced mammary branching morphogenesis was associated with increased STAT5 phosphorylation in heparanase transgenic strains, while decreased STAT5 phosphorylation was detected in Hpa-KO mice. Furthermore, high levels of heparanase/8C expression are maintained during the involution phase, associating with delayed involution. Notably, orthotopic implantation of EMT6 cells in the mammary gland of MMTV-HPA mice resulted in bigger tumors vs control. Likewise, Hpa-Tg mice are more susceptible to chemical carcinogen and die at a higher rate.Taken together, these results show that over-expression of heparanase in the mammary gland of transgenic mice enhance mammary gland development, delay involution and support tumor growth.