Journal
JOURNAL OF PATHOLOGY
Volume 246, Issue 1, Pages 41-53Publisher
WILEY
DOI: 10.1002/path.5105
Keywords
BRCA1; breast cancer; hormone signaling; ovariectomy; hormone receptor antagonists
Funding
- Dutch Cancer Society [NKI 2002-2635]
- Centre for Translational Molecular Medicine (CTMM) Breast Care project
- Netherlands Organization for Scientific Research [NWO: Cancer Genomics Netherlands (CGCNL), Cancer Systems Biology Centre (CSBC)] [VICI 91814643]
- EU [260791]
- European Research Council (ERC Synergy project CombatCancer)
- NWO
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Hereditary breast cancers in BRCA1 mutation carriers are mostly estrogen receptor alpha (ER alpha)-negative and progesterone receptor (PR)-negative; however, hormone depletion via bilateral oophorectomy does result in a marked reduction in breast cancer risk, suggesting that BRCA1-associated breast tumorigenesis is dependent on hormone signaling. We used geneticaly engineered mouse models to determine the individual influences of ER alpha and PR signaling on the development of BRCA1-deficient breast cancer. In line with the human data, BRCA1-deficient mouse mammary tumors are ER alpha-negative, and bilateral ovariectomy leads to abrogation of mammary tumor development. Hormonal replacement experiments in ovariectomized mice showed that BRCA1-deficient mammary tumor formation is promoted by estrogen but not by progesterone. In line with these data, mammary tumorigenesis was significantly delayed by the selective ER alpha downregulator fulvestrant, but not by the selective PR antagonist Org33628. Together, our results illustrate that BRCA1-associated tumorigenesis is dependent on estrogen signaling rather than on progesterone signaling, and call into question the utility of PR antagonists as a tumor prevention strategy for BRCA1 mutation carriers. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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