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Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10954-9. Epub 2003 Aug 26.

A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases.

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Department of Molecular Medicine, University of Texas Health Science Center, Institute for Drug Development, 14960 Omicron Drive, San Antonio, TX 78245, USA.


Osteoblastic bone metastases are common in prostate and breast cancer patients, but mechanisms by which tumor cells stimulate new bone formation are unclear. We identified three breast cancer cell lines that cause osteoblastic metastases in a mouse model and secrete endothelin-1. Tumor-produced endothelin-1 stimulates new bone formation in vitro and osteoblastic metastases in vivo via the endothelin A receptor. Treatment with an orally active endothelin A receptor antagonist dramatically decreased bone metastases and tumor burden in mice inoculated with ZR-75-1 cells. Tumor-produced endothelin-1 may have a major role in the establishment of osteoblastic bone metastases, and endothelin A receptor blockade represents effective treatment.

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