• Login
    View Item 
    •   Home
    • The Christie Research Publications Repository
    • All Christie Publications
    • View Item
    •   Home
    • The Christie Research Publications Repository
    • All Christie Publications
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of ChristieCommunitiesTitleAuthorsIssue DateSubmit DateSubjectsThis CollectionTitleAuthorsIssue DateSubmit DateSubjects

    My Account

    LoginRegister

    Local Links

    The Christie WebsiteChristie Library and Knowledge Service

    Statistics

    Display statistics

    Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy women

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    35701800.pdf
    Size:
    2.408Mb
    Format:
    PDF
    Description:
    Identified with Open Access button
    Download
    Authors
    Bartlett, T. E.
    Evans, I.
    Jones, A.
    Barrett, J. E.
    Haran, S.
    Reisel, D.
    Papaikonomou, K.
    Jones, L.
    Herzog, C.
    Pashayan, N.
    Simões, Bruno M
    Clarke, Robert B
    Evans, D. G.
    Ghezelayagh, T. S.
    Ponandai-Srinivasan, S.
    Boggavarapu, N. R.
    Lalitkumar, P. G.
    Howell, Sacha J
    Risques, R. A.
    Rådestad, A. F.
    Dubeau, L.
    Gemzell-Danielsson, K.
    Widschwendter, M.
    Show allShow less
    Affiliation
    Department of Statistical Science, University College London, London, WC1E 7HB, UK
    Issue Date
    2022
    
    Metadata
    Show full item record
    Abstract
    Background: Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation. Methods: In healthy premenopausal women with and without a BRCA mutation we studied (i) estrogen and progesterone levels in saliva over an entire menstrual cycle (n = 20); (ii) cancer-free normal breast-tissue from a control population who had no family or personal history of breast cancer and equivalently from BRCA1/2 mutation carriers (n = 28); triple negative breast cancer (TNBC) biopsies and healthy breast tissue taken from sites surrounding the TNBC in the same individuals (n = 14); and biopsies of ER+ve/PR+ve stage T1-T2 cancers and healthy breast tissue taken from sites surrounding the cancer in the same individuals (n = 31); and (iii) DNA methylation and DNA mutations in normal breast tissue (before and after treatment) from clinical trials that assessed the potential preventative effects of vitamins and antiprogestins (mifepristone and ulipristal acetate; n = 44). Results: Daily levels of progesterone were higher throughout the menstrual cycle of BRCA1/2 mutation carriers, raising the prospect of targeting progesterone signalling as a means of cancer risk reduction in this population. Furthermore, breast field cancerization DNA methylation signatures reflective of (i) the mitotic age of normal breast epithelium and (ii) the proportion of luminal progenitor cells were increased in breast cancers, indicating that luminal progenitor cells with elevated replicative age are more prone to malignant transformation. The progesterone receptor antagonist mifepristone reduced both the mitotic age and the proportion of luminal progenitor cells in normal breast tissue of all control women and in 64% of BRCA1/2 mutation carriers. These findings were validated by an alternate progesterone receptor antagonist, ulipristal acetate, which yielded similar results. Importantly, mifepristone reduced both the TP53 mutation frequency as well as the number of TP53 mutations in mitotic-age-responders. Conclusions: These data support the potential usage of antiprogestins for primary prevention of poor-prognostic breast cancers.
    Citation
    Bartlett TE, Evans I, Jones A, Barrett JE, Haran S, Reisel D, et al. Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy women. Vol. 14, Genome Medicine. Springer Science and Business Media LLC; 2022.
    Journal
    Genome Medicine
    URI
    http://hdl.handle.net/10541/625374
    DOI
    10.1186/s13073-022-01063-5
    PubMed ID
    35701800
    Additional Links
    https://dx.doi.org/10.1186/s13073-022-01063-5
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1186/s13073-022-01063-5
    Scopus Count
    Collections
    All Christie Publications

    entitlement

    Related articles

    • Proliferation and ovarian hormone signaling are impaired in normal breast tissues from women with BRCA1 mutations: benefit of a progesterone receptor modulator treatment as a breast cancer preventive strategy in women with inherited BRCA1 mutations.
    • Authors: Communal L, Vilasco M, Hugon-Rodin J, Courtin A, Mourra N, Lahlou N, Le Guillou M, Perrault de Jotemps M, Chauvet MP, Chaouat M, Pujol P, Feunteun J, Delaloge S, Forgez P, Gompel A
    • Issue date: 2016 Jul 19
    • Triple-negative breast cancer and PTEN (phosphatase and tensin homologue) loss are predictors of BRCA1 germline mutations in women with early-onset and familial breast cancer, but not in women with isolated late-onset breast cancer.
    • Authors: Phuah SY, Looi LM, Hassan N, Rhodes A, Dean S, Taib NA, Yip CH, Teo SH
    • Issue date: 2012 Nov 2
    • Germ-line mutations in BRCA1 or BRCA2 in the normal breast are associated with altered expression of estrogen-responsive proteins and the predominance of progesterone receptor A.
    • Authors: Mote PA, Leary JA, Avery KA, Sandelin K, Chenevix-Trench G, Kirk JA, Clarke CL, kConFab Investigators
    • Issue date: 2004 Mar
    • Relative contributions of BRCA1 and BRCA2 mutations to "triple-negative" breast cancer in Ashkenazi Women.
    • Authors: Comen E, Davids M, Kirchhoff T, Hudis C, Offit K, Robson M
    • Issue date: 2011 Aug
    • Basal cytokeratin and epidermal growth factor receptor expression are not predictive of BRCA1 mutation status in women with triple-negative breast cancers.
    • Authors: Collins LC, Martyniak A, Kandel MJ, Stadler ZK, Masciari S, Miron A, Richardson AL, Schnitt SJ, Garber JE
    • Issue date: 2009 Jul
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Contact Us
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.