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Heparanase Promotes Syndecan-1 Expression to Mediate Fibrillar Collagen and Mammographic Density in Human Breast Tissue Cultured ex vivo2.25 MB
Published VersionCC BY V4.0, Open Access
Journal article
Heparanase Promotes Syndecan-1 Expression to Mediate Fibrillar Collagen and Mammographic Density in Human Breast Tissue Cultured ex vivo
Frontiers in Cell and Developmental Biology, Vol.8, pp.1-14
2020
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.
Details
- Title
- Heparanase Promotes Syndecan-1 Expression to Mediate Fibrillar Collagen and Mammographic Density in Human Breast Tissue Cultured ex vivo
- Authors
- Xuan Huang (Author) - Queensland University of TechnologyGina Reye (Author) - Queensland University of TechnologyKonstantin I Momot (Author) - Queensland University of TechnologyTony Blick (Author) - Queensland University of TechnologyThomas Lloyd (Author) - Princess Alexandra HospitalWayne D Tilley (Author) - The University of AdelaideTheresa E Hickey (Author) - The University of AdelaideCameron E Snell (Author) - The University of QueenslandRachel K Okolicsanyi (Author) - Queensland University of TechnologyLarisa M Haupt (Author) - Queensland University of TechnologyVito Ferro (Author) - The University of QueenslandErik W Thompson (Author) - Queensland University of TechnologyHonor J Hugo (Author) - Queensland University of Technology
- Publication details
- Frontiers in Cell and Developmental Biology, Vol.8, pp.1-14
- Publisher
- Frontiers Research Foundation
- Date published
- 2020
- DOI
- 10.3389/fcell.2020.00599
- ISSN
- 2296-634X
- Copyright note
- Copyright © 2020 Huang, Reye, Momot, Blick, Lloyd, Tilley, Hickey, Snell, Okolicsanyi, Haupt, Ferro, Thompson and Hugo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
- Organisation Unit
- University of the Sunshine Coast, Queensland; School of Health and Sport Sciences - Legacy; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99516508902621
- Output Type
- Journal article
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