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dc.contributor.authorHuang, X
dc.contributor.authorReye, G
dc.contributor.authorMomot, KI
dc.contributor.authorBlick, T
dc.contributor.authorLloyd, T
dc.contributor.authorTilley, WD
dc.contributor.authorHickey, TE
dc.contributor.authorSnell, CE
dc.contributor.authorOkolicsanyi, RK
dc.contributor.authorHaupt, LM
dc.contributor.authorFerro, V
dc.contributor.authorThompson, EW
dc.contributor.authorHugo, HJ
dc.date.accessioned2021-06-28T00:53:22Z
dc.date.available2021-06-28T00:53:22Z
dc.date.issued2020
dc.identifier.issn2296-634X
dc.identifier.doi10.3389/fcell.2020.00599
dc.identifier.urihttp://hdl.handle.net/10072/405390
dc.description.abstractMammographic 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.
dc.description.peerreviewedYes
dc.publisherFrontiers Media SA
dc.relation.ispartofpagefrom599
dc.relation.ispartofjournalFrontiers in Cell and Developmental Biology
dc.relation.ispartofvolume8
dc.subject.fieldofresearchClinical Sciences
dc.subject.fieldofresearchBiochemistry and Cell Biology
dc.subject.fieldofresearchcode1103
dc.subject.fieldofresearchcode0601
dc.titleHeparanase Promotes Syndecan-1 Expression to Mediate Fibrillar Collagen and Mammographic Density in Human Breast Tissue Cultured ex vivo
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationHuang, X; Reye, G; Momot, KI; Blick, T; Lloyd, T; Tilley, WD; Hickey, TE; Snell, CE; Okolicsanyi, RK; Haupt, LM; Ferro, V; Thompson, EW; Hugo, HJ, 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, 2020, 8, pp. 599
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/
dc.date.updated2021-06-25T05:42:28Z
dc.description.versionVersion of Record (VoR)
gro.rights.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.
gro.hasfulltextFull Text
gro.griffith.authorHugo, Honor J.


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