Heparanase: a potential marker of worse prognosis in estrogen receptor-positive breast cancer

Abstract

Heparanase promotes tumor growth in breast tumors. We now evaluated heparanase protein and gene-expression status and investigated its impact on disease-free survival in order to gain better insight into the role of heparanase in ER-positive (ER+) breast cancer prognosis and to clarify its role in cell survival following chemotherapy. Using pooled analysis of gene-expression data, we found that heparanase was associated with a worse prognosis in estrogen receptor-positive (ER+) tumors (log-rank p < 10−10) and predictive to chemotherapy resistance (interaction p = 0.0001) but not hormonal therapy (Interaction p = 0.62). These results were confirmed by analysis of data from a phase III, prospective randomized trial which showed that heparanase protein expression is associated with increased risk of recurrence in ER+ breast tumors (log-rank p = 0.004). In vitro experiments showed that heparanase promoted tumor progression and increased cell viability via epithelial–mesenchymal transition, stemness, and anti-apoptosis pathways in luminal breast cancer. Taken together, our results demonstrated that heparanase is associated with worse outcomes and increased cell viability in ER+ BC.

Macrophages Upregulate Estrogen Receptor Expression in the Model of Obesity-Associated Breast Carcinoma

“…Heparanase enzyme is preferentially expressed in obesity-associated breast tumors in clinical/experimental settings [ 30 ] and associated with worse prognosis in ER+, but not ER− BC [ 52 ]. Heparanase is the only known mammalian endoglycosidase capable of cleaving heparan sulfate (HS) at the cell surface and ECM.…”

“…Of note, although heparanase is expressed by both Mϕ [ 46 , 47 , 48 , 49 ] and BC cells [ 52 ] numerous observations have repeatedly indicated that in the setting of breast tumors, carcinoma cells per se appear to represent the major cellular source of the enzyme (reviewed in [ 52 ]). Given the above notion, the secreted nature of heparanase, and the role of extracellular heparan sulfate in modulation of TLR signaling ([ 80 , 81 , 82 ]), it is plausible that in the BC under obese conditions the excessive enzyme overexpressed by the tumor cells is a main contributor to adverse activation of macrophages.…”

“…Given this complexity, our findings pointing to the ability of heparanase to dictate the ER−inducing phenotype of Mϕ in BC ( Figure 5 and Figure 6 ), and, therefore, control one of the fundamental features of hormone-dependent breast tumorigenesis, namely, the level of ER expression, suggest that modulation of the enzyme activity (rather than targeting Mϕ per se [ 95 ]) may offer an appealing alternative approach to uncouple obesity and breast cancer progression in a rapidly growing population of obese patients. Of note, a recent study (based on microarray datasets comprising >7000 BC patients, as well as prospective data from the BIG 2–98 repository [ 52 ]) demonstrated that overexpression of heparanase in BC tumors was associated with worse outcome/increased risk of recurrence in luminal (ER+) subtypes, but did not affect outcome/risk in non-luminal (ER−) subtypes [ 52 ]. This pattern of association is essentially similar to one reported for obesity, per se, which correlates with worse prognosis in BC patients bearing luminal tumors, while no such association was found in non-luminal tumors [ 13 , 14 , 26 , 27 ], and further supports the contribution of the enzyme to BC-promoting effects of obesity through Mϕ-mediated upregulation of ER.…”

“…Of note, heparanase was recently shown to sustain Mϕ reactivity in several obesity-related [ 30 , 48 , 49 ] and unrelated [ 45 , 50 , 51 ], Mϕ-driven inflammatory conditions. Worth mentioning is the fact that, similarly to obesity per se, expression of heparanase correlates with worse outcome in ER+, but not ER−, breast tumors [ 52 ]. Collectively, our findings attest to upregulation of ER expression (especially in the face of enhanced production of estrogen in fat depots) as an important, and previously unidentified, mechanism of obesity-accelerated BC progression, likely explaining the dichotomy of the obesity effects on the risk/poorer outcome between luminal (i.e., ER+) and non-luminal (i.e., ER−) BC subtypes.…”

Heparin–Superparamagnetic Iron Oxide Nanoparticles for Theranostic Applications

“…Heparin, exclusively produced by mast cells, is a more sophisticated and sulfated form of HS. Early studies evidenced HS’s higher charged congener unfractionated heparin (UFH) as an efficient heparanase inhibitor and as a substrate [ 28 , 29 , 30 , 31 ]. Early studies showed effective heparanase inhibition by UFH, even if some UFH sequences can be recognized and cleaved by heparanase [ 32 ].…”