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RASSF1A Suppression as a Potential Regulator of Mechano-Pathobiology Associated with Mammographic Density in BRCA Mutation Carriers2.35 MB
Published VersionCC BY V4.0, Open Access
Journal article
RASSF1A Suppression as a Potential Regulator of Mechano-Pathobiology Associated with Mammographic Density in BRCA Mutation Carriers
Cancers, Vol.13(13), pp.1-16
2021
PMID: 34209669
Abstract
High 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.
Details
- Title
- RASSF1A Suppression as a Potential Regulator of Mechano-Pathobiology Associated with Mammographic Density in BRCA Mutation Carriers
- Authors
- Gina Reye (Author) - Queensland University of TechnologyXuan Huang (Author) - Queensland University of TechnologyKara L Britt (Author) - Peter MacCallum Cancer CentreChristoph Meinert (Author) - Metro North Health (Australia)Tony Blick (Author) - Queensland University of TechnologyYannan Xu (Author) - Queensland University of TechnologyKonstantin I Momot (Author) - Queensland University of TechnologyThomas Lloyd (Author) - Princess Alexandra HospitalJason J Northey (Author) - University of California, San FranciscoErik W Thompson (Author) - Queensland University of TechnologyHonor J Hugo (Author) - University of the Sunshine Coast, Queensland, School of Health and Sport Sciences - Legacy
- Publication details
- Cancers, Vol.13(13), pp.1-16
- Publisher
- MDPI AG
- Date published
- 2021
- DOI
- 10.3390/cancers13133251
- ISSN
- 2072-6694
- PMID
- 34209669
- Copyright note
- 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 (https://creativecommons.org/licenses/by/4.0/).
- 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
- 99548403902621
- Output Type
- Journal article
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