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Endothelial ALK1 Is a Therapeutic Target to Block Metastatic Dissemination of Breast Cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
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2015 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 12, 2445-2456 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 75, no 12, 2445-2456 p.
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Cancer and Oncology
URN: urn:nbn:se:uu:diva-260142DOI: 10.1158/0008-5472.CAN-14-3706ISI: 000357334400006PubMedID: 26077471OAI: oai:DiVA.org:uu-260142DiVA: diva2:846729
Available from: 2015-08-18 Created: 2015-08-17 Last updated: 2016-01-15

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Cunha, Sara I.
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