期刊
NATURE MEDICINE
卷 22, 期 8, 页码 933-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4118
关键词
-
资金
- Victorian Government
- Australian National Health and Medical Research Council (NHMRC) [1016701, 1040978, 1054618]
- NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS)
- Victorian State Government through the Victorian Cancer Agency
- Victorian State Government through Operational Infrastructure Support
- National Breast Cancer Foundation (Australia) [NC-13-32, PS-15-042]
- Amgen Inc.
- Qualtrough Cancer Research Fund
- Joan Marshall Breast Cancer Research Fund
- Australian Cancer Research Foundation
- Cancer Council Victoria Scholarship
- Cancer Therapeutics CRC Top-Up Scholarship
- VCA Early Career Seed Grant [13035]
- NHMRC Fellowships [1058892, 637307, 1078730]
- NHMRC Australia Fellowship [1037230]
- National Breast Cancer Foundation [IF-12-06, PS-15-042, NC-13-32, In-15-071] Funding Source: researchfish
Individuals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1(mut/+) tissue harbors an aberrant population of luminal progenitor cells1, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis(2-5). Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling(6-10) and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis(11-13), we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK(+) and RANK-) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK+ cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK+ and not RANK-progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1mut/+ tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据