RASSF1A Suppression as a Potential Regulator of Mechano-Pathobiology Associated with Mammographic Density in BRCA Mutation Carriers

Gina Reye; Xuan Huang; Kara L Britt; Christoph Meinert; Tony Blick; Yannan Xu; Konstantin I Momot; Thomas Lloyd; Jason J Northey; Erik W Thompson; Honor J Hugo

doi:10.3390/cancers13133251

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RASSF1A Suppression as a Potential Regulator of Mechano-Pathobiology Associated with Mammographic Density in BRCA Mutation Carriers

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RASSF1A Suppression as a Potential Regulator of Mechano-Pathobiology Associated with Mammographic Density in BRCA Mutation Carriers

Gina Reye, Xuan Huang, Kara L Britt, Christoph Meinert, Tony Blick, Yannan Xu, Konstantin I Momot, Thomas Lloyd, Jason J Northey, Erik W Thompson, …

Cancers, Vol.13(13), pp.1-16

2021

DOI: https://doi.org/10.3390/cancers13133251

PMCID: PMC8269117

PMID: 34209669

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Abstract

breast cancer

mammographic density

RASSF1A

stiffness

BRCA1/2 mutations

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.

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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 Technology
Xuan Huang (Author) - Queensland University of Technology
Kara L Britt (Author) - Peter MacCallum Cancer Centre
Christoph Meinert (Author) - Metro North Health (Australia)
Tony Blick (Author) - Queensland University of Technology
Yannan Xu (Author) - Queensland University of Technology
Konstantin I Momot (Author) - Queensland University of Technology
Thomas Lloyd (Author) - Princess Alexandra Hospital
Jason J Northey (Author) - University of California, San Francisco
Erik W Thompson (Author) - Queensland University of Technology
Honor 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; PMC8269117
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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Web Of Science research areas: Oncology

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