1. Cancer Biology and Genetics Program,
2. Department of Medicine,
3. Molecular Cytology Core Facility, and,
4. Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
5. These authors contributed equally to this work.
6. Present addresses: Hemato-Oncology Institute, Hospital Clinic de Barcelona, 08036 Barcelona, Spain (C.N.); Oncology Programme, Institute for Research in Biomedecine, Barcelona Science Park and University of Barcelona, 08028 Barcelona, Spain (R.R.G.).

Correspondence to: Joan Massagué^1,4 Correspondence and requests for materials should be addressed to J.M. (Email: j-massague@ski.mskcc.org).

Abstract

Metastasis entails numerous biological functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacological approaches, we show that the epidermal growth factor receptor ligand epiregulin, the cyclooxygenase COX2, and the matrix metalloproteinases 1 and 2, when expressed in human breast cancer cells, collectively facilitate the assembly of new tumour blood vessels, the release of tumour cells into the circulation, and the breaching of lung capillaries by circulating tumour cells to seed pulmonary metastasis. These findings reveal how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biological activities may be therapeutically targeted with specific drug combinations.

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