Heparanase Mechanisms in Brain - Metastatic Breast Cancer

Abstract

Abstract : Heparanase (HPSE) is a potent pro-tumorigenic, pro-angiogenic, and pro-metastatic enzyme over-expressed in brain metastatic breast cancer (BMBC). However, regulation of the heparanase gene is poorly understood. We hypothesized that heparanase represents a potential target for the development of novel therapies for BMBC, whose gene expression and modalities can be regulated by microRNA. Using miRanda and RNAhybrid, we identified microRNA-1258 (miR-1258) to directly target HPSE and suppress BMBC. We demonstrated miR-1258 levels to inversely correlate with heparanase expression, enzymatic activity, and cancer cell metastatic propensities - lowest in highly aggressive BMBC cell variants, compared to either non-tumorigenic or non-metastatic human mammary epithelial cells. These findings were validated by analyses of miR-1258 and heparanase content in paired clinical tissues - normal mammary gland versus invasive ductal carcinoma, and primary breast cancer versus BMBC. Furthermore, we demonstrated that miR-1258 inhibits the expression and activity of heparanase in BMBC cells, and rescue experiments modulating heparanase blocked miR-1258 - mediated phenotypic effects. Finally, we showed that miR-1258 stably expressed in BMBC cells significantly inhibited heparanase, in vitro cell invasion, and suppressed experimental brain metastasis by 74%. These findings introduce a new concept that links microRNA mechanisms with brain metastatic breast cancer by downregulating HPSE, providing the groundwork for heparanase-based therapeutics in patients with brain metastases, BMBC in particular.