靶向孕激素信号通路可预防转移性卵巢癌。
Targeting progesterone signaling prevents metastatic ovarian cancer.
机构信息
Department of Biochemistry and Molecular Biology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202.
Department of Pathology, School of Medicine, Keimyung University, 41931 Daegu, Republic of Korea.
出版信息
Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):31993-32004. doi: 10.1073/pnas.2013595117. Epub 2020 Dec 1.
Abstract
Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the gene.
摘要
有效的癌症预防需要发现和干预对癌症发展至关重要的因素。在这里，我们表明卵巢孕激素是一种关键的内源性因素，它可诱导在高级别浆液性卵巢癌（HGSC）的小鼠模型中发生的原发性肿瘤发展为转移性卵巢癌，HGSC 是最常见且最致命的卵巢癌类型。通过药理学抑制剂米非司酮或孕激素受体（PR）的基因缺失来阻断孕激素信号，可有效抑制 HGSC 的发展及其腹膜转移。引人注目的是，米非司酮治疗显著提高了小鼠的存活率（约 18 个人类年）。因此，靶向孕激素/PR 信号可能提供一种有效的化学预防策略，特别是在携带基因有害突变的高危女性人群中。
相似文献
1
Targeting progesterone signaling prevents metastatic ovarian cancer.靶向孕激素信号通路可预防转移性卵巢癌。
Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):31993-32004. doi: 10.1073/pnas.2013595117. Epub 2020 Dec 1.
2
Mifepristone mediates anti-proliferative effect on ovarian mesenchymal stem/stromal cells from female BRCA carriers.米非司酮介导对 BRCA 携带者来源的卵巢间充质干细胞/基质细胞的抗增殖作用。
Acta Obstet Gynecol Scand. 2019 Feb;98(2):250-261. doi: 10.1111/aogs.13485. Epub 2018 Nov 15.
3
Quantitative analysis of γ-H2AX and p53 nuclear expression levels in ovarian and fallopian tube epithelium from risk-reducing salpingo-oophorectomies in BRCA1 and BRCA2 mutation carriers.对BRCA1和BRCA2突变携带者进行降低风险的输卵管卵巢切除术所获得的卵巢和输卵管上皮中γ-H2AX和p53核表达水平的定量分析。
Int J Gynecol Pathol. 2014 May;33(3):309-16. doi: 10.1097/PGP.0b013e31829c673b.
4
Cancer precursor lesions in the BRCA population at the time of prophylactic salpingo-oophorectomy: Accuracy of assessment and potential surrogate marker for prevention.预防性输卵管卵巢切除时BRCA人群中的癌前病变：评估准确性及预防的潜在替代标志物
Gynecol Oncol. 2015 Aug;138(2):235-7. doi: 10.1016/j.ygyno.2015.06.014. Epub 2015 Jun 10.
5
BRCA mutation testing for first-degree relatives of women with high-grade serous ovarian cancer.BRCA 突变检测用于高分级浆液性卵巢癌女性的一级亲属。
Gynecol Oncol. 2019 Mar;152(3):459-464. doi: 10.1016/j.ygyno.2018.10.014.
6
Fallopian Tube Lesions in Women at High Risk for Ovarian Cancer: A Multicenter Study.高危人群的输卵管病变与卵巢癌：一项多中心研究。
Cancer Prev Res (Phila). 2018 Nov;11(11):697-706. doi: 10.1158/1940-6207.CAPR-18-0009. Epub 2018 Sep 19.
7
BRCA mutational status, initial disease presentation, and clinical outcome in high-grade serous advanced ovarian cancer: a multicenter study.高级别浆液性晚期卵巢癌的BRCA突变状态、初始疾病表现及临床结局：一项多中心研究
Am J Obstet Gynecol. 2017 Sep;217(3):334.e1-334.e9. doi: 10.1016/j.ajog.2017.05.036. Epub 2017 May 23.
8
Endometrium is not the primary site of origin of pelvic high-grade serous carcinoma in BRCA1 or BRCA2 mutation carriers.BRCA1 或 BRCA2 突变携带者的盆部高级别浆液性癌并非起源于子宫内膜。
Mod Pathol. 2013 Apr;26(4):572-8. doi: 10.1038/modpathol.2012.169. Epub 2012 Oct 19.
9
Outcomes of Incidental Fallopian Tube High-Grade Serous Carcinoma and Serous Tubal Intraepithelial Carcinoma in Women at Low Risk of Hereditary Breast and Ovarian Cancer.遗传性乳腺癌和卵巢癌低风险女性的偶然发现的输卵管高级别浆液性癌和输卵管上皮内浆液性癌的预后
Int J Gynecol Cancer. 2016 Mar;26(3):431-6. doi: 10.1097/IGC.0000000000000639.
10
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.携带BRCA1基因突变的女性正常乳腺组织中的细胞增殖及卵巢激素信号传导受损：孕激素受体调节剂治疗作为遗传性BRCA1基因突变女性乳腺癌预防策略的益处。
Oncotarget. 2016 Jul 19;7(29):45317-45330. doi: 10.18632/oncotarget.9638.
引用本文的文献
1
Epigenetic signatures in surrogate tissues are able to assess cancer risk and indicate the efficacy of preventive measures.替代组织中的表观遗传特征能够评估癌症风险并表明预防措施的效果。
Commun Med (Lond). 2025 Apr 2;5(1):97. doi: 10.1038/s43856-025-00779-w.
2
Estrogens and breast cancer.雌激素与乳腺癌
Ann Oncol. 2025 Feb;36(2):134-148. doi: 10.1016/j.annonc.2024.10.824. Epub 2024 Nov 8.
3
Novel frontiers in urogenital cancers: from molecular bases to preclinical models to tailor personalized treatments in ovarian and prostate cancer patients.泌尿生殖系统癌症的新前沿：从分子基础到临床前模型，为卵巢癌和前列腺癌患者制定个性化治疗方案。
J Exp Clin Cancer Res. 2024 May 15;43(1):146. doi: 10.1186/s13046-024-03065-0.
4
BRCA1 and Its Vulnerable C-Terminal BRCT Domain: Structure, Function, Genetic Mutations and Links to Diagnosis and Treatment of Breast and Ovarian Cancer.BRCA1及其易损的C端BRCT结构域：结构、功能、基因突变以及与乳腺癌和卵巢癌诊断与治疗的关联
Pharmaceuticals (Basel). 2024 Mar 4;17(3):333. doi: 10.3390/ph17030333.
5
Natural Killer Cell Dysfunction in Premenopausal Mutation Carriers: A Potential Mechanism for Ovarian Carcinogenesis.绝经前突变携带者的自然杀伤细胞功能障碍：卵巢癌发生的一种潜在机制。
Cancers (Basel). 2024 Mar 18;16(6):1186. doi: 10.3390/cancers16061186.
6
Establishment of a steroid binding assay for goldfish membrane progesterone receptor (mPR) by coupling with graphene quantum dots (GQDs).通过与石墨烯量子点（GQDs）偶联建立金鱼膜孕酮受体（mPR）的类固醇结合测定法。
Fish Physiol Biochem. 2024 Jun;50(3):1331-1339. doi: 10.1007/s10695-024-01315-8. Epub 2024 Feb 8.
7
Effects of the Overexpression of Progesterone Receptors on a Precancer p53 and Rb-Defective Human Fallopian Tube Epithelial Cell Line.孕激素受体过表达对具有癌前 p53 和 Rb 缺陷的人输卵管上皮细胞系的影响。
Int J Mol Sci. 2023 Jul 23;24(14):11823. doi: 10.3390/ijms241411823.
8
Crosstalk between ferroptosis and steroid hormone signaling in gynecologic cancers.妇科癌症中细胞铁死亡与类固醇激素信号传导之间的串扰。
Front Mol Biosci. 2023 Jul 4;10:1223493. doi: 10.3389/fmolb.2023.1223493. eCollection 2023.
9
Reevaluating the Role of Progesterone in Ovarian Cancer: Is Progesterone Always Protective?重新评估孕激素在卵巢癌中的作用：孕激素总是保护性的吗？
Endocr Rev. 2023 Nov 9;44(6):1029-1046. doi: 10.1210/endrev/bnad018.
10
Clinical factors affecting the long-term survival of breast cancer patients.影响乳腺癌患者长期生存的临床因素。
J Int Med Res. 2023 Mar;51(3):3000605231164004. doi: 10.1177/03000605231164004.
本文引用的文献
1
Dexamethasone in Hospitalized Patients with Covid-19.地塞米松在 COVID-19 住院患者中的应用。
N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17.
2
In vivo modeling of metastatic human high-grade serous ovarian cancer in mice.在体建模转移性人高级别浆液性卵巢癌的小鼠。
PLoS Genet. 2020 Jun 4;16(6):e1008808. doi: 10.1371/journal.pgen.1008808. eCollection 2020 Jun.
3
Clinicopathological Characteristics and Breast Cancer-Specific Survival of Patients With Single Hormone Receptor-Positive Breast Cancer.单一激素受体阳性乳腺癌患者的临床病理特征和乳腺癌特异性生存分析。
JAMA Netw Open. 2020 Jan 3;3(1):e1918160. doi: 10.1001/jamanetworkopen.2019.18160.
4
Both fallopian tube and ovarian surface epithelium are cells-of-origin for high-grade serous ovarian carcinoma.输卵管和卵巢表面上皮都是高级别浆液性卵巢癌的起源细胞。
Nat Commun. 2019 Nov 26;10(1):5367. doi: 10.1038/s41467-019-13116-2.
5
Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer.尼拉帕利联合一线化疗及维持治疗卵巢癌
N Engl J Med. 2019 Dec 19;381(25):2403-2415. doi: 10.1056/NEJMoa1909707. Epub 2019 Sep 28.
6
Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer.尼拉帕利治疗新诊断的晚期卵巢癌患者。
N Engl J Med. 2019 Dec 19;381(25):2391-2402. doi: 10.1056/NEJMoa1910962. Epub 2019 Sep 28.
7
Deep Metabolomics of a High-Grade Serous Ovarian Cancer Triple-Knockout Mouse Model.高级别浆液性卵巢癌三敲除小鼠模型的深度代谢组学研究。
J Proteome Res. 2019 Aug 2;18(8):3184-3194. doi: 10.1021/acs.jproteome.9b00263. Epub 2019 Jul 10.
8
Progesterone-Related Immune Modulation of Pregnancy and Labor.孕酮相关的妊娠与分娩免疫调节
Front Endocrinol (Lausanne). 2019 Mar 29;10:198. doi: 10.3389/fendo.2019.00198. eCollection 2019.
9
Cell Origins of High-Grade Serous Ovarian Cancer.高级别浆液性卵巢癌的细胞起源
Cancers (Basel). 2018 Nov 12;10(11):433. doi: 10.3390/cancers10110433.
10
Ovarian cancer statistics, 2018.卵巢癌统计数据，2018 年。
CA Cancer J Clin. 2018 Jul;68(4):284-296. doi: 10.3322/caac.21456. Epub 2018 May 29.
Zotero 插件