Oncology Abstracts

Mammographic density (MD) is an independent risk factor for breast cancer, however what molecule or pathway within MD tissue contributes to this risk? High MD is characterized by an abundance of connective tissue stroma which is rich in heparan sulfate proteoglycans (HSPGs). Of these, SDC1 and SDC4 are upregulated in breast cancer, and we have observed a significantly higher abundance of these proteins in high vs low MD pair-wise comparisons from breast tissue from 8 individual women. Heparanase promotes HSPG-bound growth factor release via cleavage of HS chains leading to shedding and upregulation of SDC expression. Heparanase is upregulated by estrogen, as is MD, which decreases following menopause and tamoxifen therapy, and increases with HRT, implying MD and its associated breast cancer risk are modifiable. We sought to examine whether heparanase expression determines SDC1/4 protein expression and thus MD by directly modulating this enzyme in human mammary tissue grown ex-vivo. Patient-derived explants (PDEs) from prophylactic mastectomy material were supplemented with media containing estradiol or estradiol/tamoxifen, or the antagonistic heparanase mimetic PG545. RNA was collected for QRT-PCR, and remaining tissue used for IHC. Conditioned media was collected from the explants and tested via ELISA for shed SDC1 as an indicator of heparanase enzyme activity. Mammographic density change was measured using a single-sided MRI machine (NMR-MOUSE). Heparanase inhibition via PG545 in PDEs led to a decrease in shed SDC1 in explant conditioned media, a reduction in MMP-9 and SDC1 gene expression and a reduction in SDC1 protein in glandular tissue. PG545 treatment also led to a significant drop in NMR T1 values equating to a reduction in mammographic density. Hormone treatment led to an expected increase in TFF-1, but also a positive linear correlation between heparanase and SDC1 or heparanase and SDC4 expression. These effects were uncoupled by tamoxifen. The results of this study suggest that estrogen maintains MD via its positive effect on heparanase and subsequent syndecan 1 and 4 protein abundance. Agents designed to thwart this pathway in vivo have the potential to prevent breast cancer developing in women with high mammographic density.