Huang Xuan, Reye Gina, Momot Konstantin I, Blick Tony, Lloyd Thomas, Tilley Wayne D, Hickey Theresa E, Snell Cameron E, Okolicsanyi Rachel K, Haupt Larisa M, Ferro Vito, Thompson Erik W, Hugo Honor J
Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Australia.
Translational Research Institute, Woolloongabba, QLD, Australia.
Front Cell Dev Biol. 2020 Jul 14;8:599. doi: 10.3389/fcell.2020.00599. eCollection 2020.
Mammographic density (MD) is a strong and independent factor for breast cancer (BC) risk and is increasingly associated with BC progression. We have previously shown in mice that high MD, which is characterized by the preponderance of a fibrous stroma, facilitates BC xenograft growth and metastasis. This stroma is rich in extracellular matrix (ECM) factors, including heparan sulfate proteoglycans (HSPGs), such as the BC-associated syndecan-1 (SDC1). These proteoglycans tether growth factors, which are released by heparanase (HPSE). MD is positively associated with estrogen exposure and, in cell models, estrogen has been implicated in the upregulation of HPSE, the activity of which promotes SDC expression. Herein we describe a novel measurement approach (single-sided NMR) using a patient-derived explant (PDE) model of normal human (female) mammary tissue cultured to investigate the role(s) of HPSE and SDC1 on MD. Relative HSPG gene and protein analyses determined in patient-paired high vs. low MD tissues identified SDC1 and SDC4 as potential mediators of MD. Using the PDE model we demonstrate that HPSE promotes SDC1 rather than SDC4 expression and cleavage, leading to increased MD. In this model system, synstatin (SSTN), an SDC1 inhibitory peptide designed to decouple SDC1-ITGαvβ3 parallel collagen alignment, reduced the abundance of fibrillar collagen as assessed by picrosirius red viewed under polarized light, and reduced MD. Our results reveal a potential role for HPSE in maintaining MD via its direct regulation of SDC1, which in turn physically tethers collagen into aligned fibers characteristic of MD. We propose that inhibitors of HPSE and/or SDC1 may afford an opportunity to reduce MD in high BC risk individuals and reduce MD-associated BC progression in conjunction with established BC therapies.
乳腺密度（MD）是乳腺癌（BC）风险的一个强大且独立的因素，并且越来越多地与BC进展相关。我们之前在小鼠中表明，以纤维基质占优势为特征的高MD促进了BC异种移植瘤的生长和转移。这种基质富含细胞外基质（ECM）因子，包括硫酸乙酰肝素蛋白聚糖（HSPG），如与BC相关的syndecan-1（SDC1）。这些蛋白聚糖束缚生长因子，而生长因子由乙酰肝素酶（HPSE）释放。MD与雌激素暴露呈正相关，并且在细胞模型中，雌激素与HPSE的上调有关，其活性促进SDC表达。在此，我们描述了一种新的测量方法（单侧核磁共振），使用培养的正常人类（女性）乳腺组织的患者来源外植体（PDE）模型来研究HPSE和SDC1在MD中的作用。在患者配对的高MD组织与低MD组织中进行的相对HSPG基因和蛋白质分析确定SDC1和SDC4为MD的潜在介质。使用PDE模型，我们证明HPSE促进SDC1而非SDC4的表达和裂解，导致MD增加。在这个模型系统中，synstatin（SSTN）是一种SDC1抑制肽，旨在解耦SDC1-ITGαvβ3平行胶原排列，通过偏振光下观察的天狼星红评估，减少了纤维状胶原的丰度，并降低了MD。我们的结果揭示了HPSE通过其对SDC1的直接调节在维持MD中的潜在作用，而SDC1又将胶原物理束缚成MD特征性的排列纤维。我们提出，HPSE和/或SDC1的抑制剂可能为降低高BC风险个体的MD以及与既定的BC治疗联合减少与MD相关的BC进展提供机会。
