Abstract

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 ex vivo 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.

Highlights

  • In Australia, mammographic screening reduces mortality by around 50% for screening participants (Roder et al, 2008; Nickson et al, 2012)

  • RT-qPCR Data As shown in Figure 1, RT-qPCR assessment of a range of heparan sulfate proteoglycan (HSPG) showed that mRNA levels of SDC1 and SDC4 were significantly more abundant, 14 and 7-fold higher, respectively, in high mammographic density (HMD)

  • Given that increased stroma is characteristic of HMD (Huo et al, 2015), postulated in this study to be driven by HSPG abundance, SDC1 and SDC4 were taken forward for further analysis

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Summary

Introduction

In Australia, mammographic screening reduces mortality by around 50% for screening participants (Roder et al, 2008; Nickson et al, 2012). Mammographic test sensitivity is impaired in women who have high mammographic density (HMD), where the dense area on the mammogram can mask BC-associated features, contributing to an increase in “interval cancers” that arise within 1–2 years of a “clear” mammogram, and an increase in false negative and false positive screens (Nelson et al, 2016). After adjusting for age and body mass index (BMI), on a population basis HMD is one of the strongest risk factors for BC. In addition to increased BC risk, evidence is emerging that HMD is associated with increased BC recurrence (Hwang et al, 2007; Cil et al, 2009; Shawky et al, 2015, 2019; Huang et al, 2016) and treatment resistance (Elsamany et al, 2015). Interventions that reduce MD may offer new avenues for the prevention, diagnosis and treatment of BC

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