期刊
CANCER RESEARCH
卷 75, 期 12, 页码 2445-2456出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-3706
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资金
- Consolidator Grant from the European Research Council (the TUMORGAN project)
- Swedish Research Council
- Swedish Cancer Society
- STARGET consortium (a Swedish Research Council Linnaeus network)
- BioCARE
- Lund University
- BRECT
- Karolinska Institutet
- Stockholm County Council
- research funds at Radiumhemmet
- Karolinska University Hospital
Exploration of new strategies for the prevention of breast cancer metastasis is justifiably at the center of clinical attention. In this study, we combined a computational biology approach with mechanism-based preclinical trials to identify inhibitors of activin-like receptor kinase (ALK) 1 as effective agents for blocking angiogenesis and metastasis in breast cancer. Pharmacologic targeting of ALK1 provided long-term therapeutic benefit in mouse models of mammary carcinoma, accompanied by strikingly reduced metastatic colonization as a monotherapy or part of combinations with chemotherapy. Gene-expression analysis of breast cancer specimens from a population-based nested case-control study encompassing 768 subjects defined endothelial expression of ALK1 as an independent and highly specific prognostic factor for metastatic manifestation, a finding that was corroborated in an independent clinical cohort. Overall, our results suggest that pharmacologic inhibition of endothelial ALK1 constitutes a tractable strategy for interfering with metastatic dissemination of breast cancer. (C) 2015 AACR.
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