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dc.contributor.authorReye, Gina
dc.contributor.authorHuang, Xuan
dc.contributor.authorBritt, Kara L
dc.contributor.authorMeinert, Christoph
dc.contributor.authorBlick, Tony
dc.contributor.authorXu, Yannan
dc.contributor.authorMomot, Konstantin I
dc.contributor.authorLloyd, Thomas
dc.contributor.authorNorthey, Jason J
dc.contributor.authorThompson, Erik W
dc.contributor.authorHugo, Honor J
dc.date.accessioned2021-07-13T05:01:48Z
dc.date.available2021-07-13T05:01:48Z
dc.date.issued2021
dc.identifier.issn2072-6694
dc.identifier.doi10.3390/cancers13133251
dc.identifier.urihttp://hdl.handle.net/10072/405903
dc.description.abstractHigh mammographic density (MD) increases breast cancer (BC) risk and creates a stiff tissue environment. BC risk is also increased in BRCA1/2 gene mutation carriers, which may be in part due to genetic disruption of the tumour suppressor gene Ras association domain family member 1 (RASSF1A), a gene that is also directly regulated by tissue stiffness. High MD combined with BRCA1/2 mutations further increase breast cancer risk, yet BRCA1/2 mutations alone or in combination do not increase MD. The molecular basis for this additive effect therefore remains unclear. We studied the interplay between MD, stiffness, and BRCA1/2 mutation status in human mammary tissue obtained after prophylactic mastectomy from women at risk of developing BC. Our results demonstrate that RASSF1A expression increased in MCF10DCIS.com cell cultures with matrix stiffness up until ranges corresponding with BiRADs 4 stiffnesses (~16 kPa), but decreased in higher stiffnesses approaching malignancy levels (>50 kPa). Similarly, higher RASSF1A protein was seen in these cells when co-cultivated with high MD tissue in murine biochambers. Conversely, local stiffness, as measured by collagen I versus III abundance, repressed RASSF1A protein expression in BRCA1, but not BRCA2 gene mutated tissues; regional density as measured radiographically repressed RASSF1A in both BRCA1/2 mutated tissues. The combinatory effect of high MD and BRCA mutations on breast cancer risk may be due to RASSF1A gene repression in regions of increased tissue stiffness.
dc.description.peerreviewedYes
dc.languageeng
dc.publisherMDPI AG
dc.relation.ispartofpagefrom3251
dc.relation.ispartofissue13
dc.relation.ispartofjournalCancers
dc.relation.ispartofvolume13
dc.subject.fieldofresearchOncology and carcinogenesis
dc.subject.fieldofresearchCancer therapy (excl. chemotherapy and radiation therapy)
dc.subject.fieldofresearchcode3211
dc.subject.fieldofresearchcode321104
dc.subject.keywordsBRCA1/2 mutations
dc.subject.keywordsRASSF1A
dc.subject.keywordsbreast cancer
dc.subject.keywordsmammographic density
dc.subject.keywordsstiffness
dc.titleRASSF1A Suppression as a Potential Regulator of Mechano-Pathobiology Associated with Mammographic Density in BRCA Mutation Carriers
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationReye, G; Huang, X; Britt, KL; Meinert, C; Blick, T; Xu, Y; Momot, KI; Lloyd, T; Northey, JJ; Thompson, EW; Hugo, HJ, RASSF1A Suppression as a Potential Regulator of Mechano-Pathobiology Associated with Mammographic Density in BRCA Mutation Carriers, Cancers, 2021, 13 (13), pp. 3251-3251
dcterms.dateAccepted2021-06-26
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/
dc.date.updated2021-07-12T03:39:45Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorHugo, Honor J.


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