{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T13:11:41Z","timestamp":1791983501277,"version":"4.4.0"},"reference-count":26,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T00:00:00Z","timestamp":1710720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Research Council (ERC)","award":["742432"],"award-info":[{"award-number":["742432"]}]},{"name":"Eve Appeal","award":["742432"],"award-info":[{"award-number":["742432"]}]},{"name":"Lena W\u00e4ppling\u2019s Foundation 2023","award":["742432"],"award-info":[{"award-number":["742432"]}]},{"name":"U.S. Department of Defense W81XWH2210390","award":["742432"],"award-info":[{"award-number":["742432"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in BRCA1 mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germline BRCA1 mutation in the context of cancer immunosurveillance of CD3\u2212 CD56+ natural killer (NK) cells. Methods: Premenopausal BRCA1 mutation carriers versus age-matched non-carriers were compared. Daily urinary 5\u03b2-pregnanediol levels were used to determine progesterone metabolomics across an ovarian cycle. Using peripherally acquired NK cells the cell-mediated cytotoxicity of tumor targets (OVCAR-3, K-562) was determined using live cellular impedance (xCELLigence\u00ae) and multicolor flow cytometry. Hypoxia-inducible factor 1-alpha (HIF-1\u03b1) immunohistochemistry of cancer-free fallopian tube specimens allowed a comparison of proximal versus distal portions. Utilizing these findings the role of environmental factors relevant to the fimbrial fallopian tube (progesterone, hypoxia) on NK cell functional activity were studied in an ovarian phase-specific manner. Results: BRCA1 mutation carriers demonstrate a differential progesterone metabolome with a phase-specific reduction of peripheral NK cell functional activity. Progesterone exposure further impairs NK cell-mediated cytotoxicity in a dose-dependent manner, which is reversed with the addition of mifepristone (1.25 \u00b5M). The fimbrial fallopian tube demonstrated significantly higher HIF-1\u03b1 staining, particularly in BRCA1 mutation carriers, reflecting a site-specific \u2018hypoxic niche\u2019. Exposure to hypoxic conditions (1% O2) can further impair tumor cytotoxicity in high-risk carriers. Conclusions: Phase-specific differential NK cell activity in BRCA1 mutation carriers, either systemically or locally, may favor site-specific pre-invasive carcinogenesis. These cumulative effects across a reproductive lifecycle in high-risk carriers can have a detrimental effect further supporting epidemiological evidence for ovulation inhibition.<\/jats:p>","DOI":"10.3390\/cancers16061186","type":"journal-article","created":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T04:25:15Z","timestamp":1710735915000},"page":"1186","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Natural Killer Cell Dysfunction in Premenopausal BRCA1 Mutation Carriers: A Potential Mechanism for Ovarian Carcinogenesis"],"prefix":"10.3390","volume":"16","author":[{"given":"Shaun","family":"Haran","sequence":"first","affiliation":[{"name":"Department of Women\u2019s Cancer, Elizabeth Garrett Anderson (EGA) Institute for Women\u2019s Health, University College London (UCL), 72 Huntley Street, London WC1E 6DD, UK"},{"name":"Department of Gynaeoncology, University College London Hospitals (UCLH) NHS Trust, London NW1 2BU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kantaraja","family":"Chindera","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s Cancer, Elizabeth Garrett Anderson (EGA) Institute for Women\u2019s Health, University College London (UCL), 72 Huntley Street, London WC1E 6DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May","family":"Sabry","sequence":"additional","affiliation":[{"name":"Institute of Immunity & Transplantation, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nafisa","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Department of Cellular Pathology, University College London Hospitals (UCLH) NHS Trust, London NW1 2BU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupali","family":"Arora","sequence":"additional","affiliation":[{"name":"Department of Cellular Pathology, University College London Hospitals (UCLH) NHS Trust, London NW1 2BU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Zubiak","sequence":"additional","affiliation":[{"name":"Institute of Immunity & Transplantation, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E.","family":"Bartlett","sequence":"additional","affiliation":[{"name":"Department of Statistical Science, University College London, London WC1E 7HB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0225-3154","authenticated-orcid":false,"given":"Iona","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s Cancer, Elizabeth Garrett Anderson (EGA) Institute for Women\u2019s Health, University College London (UCL), 72 Huntley Street, London WC1E 6DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s Cancer, Elizabeth Garrett Anderson (EGA) Institute for Women\u2019s Health, University College London (UCL), 72 Huntley Street, London WC1E 6DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Reisel","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s Cancer, Elizabeth Garrett Anderson (EGA) Institute for Women\u2019s Health, University College London (UCL), 72 Huntley Street, London WC1E 6DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Herzog","sequence":"additional","affiliation":[{"name":"European Translational Oncology Prevention and Screening (EUTOPS) Institute, University of Innsbruck, 6060 Hall in Tirol, Austria"},{"name":"Research Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4567-2364","authenticated-orcid":false,"given":"Twana","family":"Alkasalias","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, Division of Obstetrics and Gynecology, Karolinska Institutet, Karolinska University Hospital, 14186 Stockholm, Sweden"},{"name":"General Directorate of Scientific Research Center, Salahaddin University-Erbil, Erbil 44002, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Newman","sequence":"additional","affiliation":[{"name":"Precision Analytical Inc., McMinnville, OR 97128, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2811-8281","authenticated-orcid":false,"given":"Jaeyeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, School of Medicine, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1068-9732","authenticated-orcid":false,"given":"Angelique Fl\u00f6ter","family":"R\u00e5destad","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, Division of Obstetrics and Gynecology, Karolinska Institutet, Karolinska University Hospital, 14186 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6516-1444","authenticated-orcid":false,"given":"Kristina","family":"Gemzell-Danielsson","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, Division of Obstetrics and Gynecology, Karolinska Institutet, Karolinska University Hospital, 14186 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam N.","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s Cancer, Elizabeth Garrett Anderson (EGA) Institute for Women\u2019s Health, University College London (UCL), 72 Huntley Street, London WC1E 6DD, UK"},{"name":"Department of Gynaeoncology, University College London Hospitals (UCLH) NHS Trust, London NW1 2BU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Dubeau","sequence":"additional","affiliation":[{"name":"Department of Pathology, Keck School of Medicine, USC Norris Comprehensive Cancer Centre, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2600-5024","authenticated-orcid":false,"given":"Mark W.","family":"Lowdell","sequence":"additional","affiliation":[{"name":"Institute of Immunity & Transplantation, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7778-8380","authenticated-orcid":false,"given":"Martin","family":"Widschwendter","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s Cancer, Elizabeth Garrett Anderson (EGA) Institute for Women\u2019s Health, University College London (UCL), 72 Huntley Street, London WC1E 6DD, UK"},{"name":"European Translational Oncology Prevention and Screening (EUTOPS) Institute, University of Innsbruck, 6060 Hall in Tirol, Austria"},{"name":"Research Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria"},{"name":"Department of Women\u2019s and Children\u2019s Health, Division of Obstetrics and Gynecology, Karolinska Institutet, Karolinska University Hospital, 14186 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1001\/jamaoncol.2022.0476","article-title":"Expansion of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic Variants","volume":"8","author":"Momozawa","year":"2022","journal-title":"JAMA Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/ni1582","article-title":"Functions of natural killer cells","volume":"9","author":"Vivier","year":"2008","journal-title":"Nat. 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