Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-10, Vol.109 (40), p.E2707-E2716
• Main Authors: Schito, Luana, Rey, Sergio, Tafani, Marco, Zhang, Huafeng, Wong, Carmen Chak-Lui, Russo, Andrea, Russo, Matteo A, Semenza, Gregg L
• Format: Article
• Language: English
• Subjects: angiogenesis; Benzamides; Biological Sciences; biopsy; breast neoplasms; Breast Neoplasms - metabolism; Breast Neoplasms - physiopathology; Cell Hypoxia - physiology; Cell Line, Tumor; chemotaxis; Chromatin Immunoprecipitation; clinical trials; digoxin; Digoxin - pharmacology; endothelial cells; Female; genes; Humans; hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1 - antagonists & inhibitors; Hypoxia-Inducible Factor 1 - physiology; Imatinib Mesylate; Immunoblotting; Immunohistochemistry; Luciferases; Lymphangiogenesis - drug effects; Lymphatic Metastasis - physiopathology; metastasis; mice; mortality; neoplasm cells; patients; Piperazines - pharmacology; platelet-derived growth factor; PNAS Plus; Proto-Oncogene Proteins c-sis - metabolism; Pyrimidines - pharmacology; RNA, Small Interfering - metabolism; transcriptional activation; Transcriptional Activation - drug effects; Transcriptional Activation - physiology; tyrosine
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1214019109

Lymphatic dissemination from the primary tumor is a major mechanism by which breast cancer cells access the systemic circulation, resulting in distant metastasis and mortality. Numerous studies link activation of hypoxia-inducible factor 1 (HIF-1) with tumor angiogenesis, metastasis, and patient mortality. However, the role of HIF-1 in lymphatic dissemination is poorly understood. In this study, we show that HIF-1 promotes lymphatic metastasis of breast cancer by direct transactivation of the gene encoding platelet-derived growth factor B (PDGF-B), which has proliferative and chemotactic effects on lymphatic endothelial cells. Lymphangiogenesis and lymphatic metastasis in mice bearing human breast cancer orthografts were blocked by administration of the HIF-1 inhibitor digoxin or the tyrosine kinase inhibitor imatinib. Immunohistochemical analysis of human breast cancer biopsies demonstrated colocalization of HIF-1α and PDGF-B, which were correlated with lymphatic vessel area and histological grade. Taken together, these data provide experimental support for breast cancer clinical trials targeting HIF-1 and PDGF-B.