1. ¹Transgenic Oncogenesis Group, Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
2. ²Division of Cancer Biology and Department of Medicine, NorthShore University HealthSystem Research Institute, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA

Correspondence: Dr JE Green, Transgenic Oncogenesis Group, Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Building 37, Room 4054, Bethesda, MD 20982, USA. E-mail: jegreen@nih.gov

Received 20 October 2008; Revised 11 March 2009; Accepted 31 March 2009; Published online 22 June 2009.

Abstract

B-lymphoma Moloney murine leukaemia virus insertion region-1 (BMI1) is a member of the polycomb group of transcription repressors, which functions in stem cell maintenance and oncogenesis through the inhibition of the INK4A/ARF tumour suppressor locus. Overexpression of BMI1 is associated with poor prognosis in several human cancers, including breast cancer. We have previously shown that BMI1 collaborates with H-RAS to induce transformation of MCF10A human mammary epithelial cells through dysregulation of multiple growth pathways independent of the INK4A/ARF locus. In this study, we show that BMI1 collaborates with H-RAS to promote increased proliferation, invasion and resistance to apoptosis in vitro, and an increased rate of spontaneous metastases from mammary fat pad xenografts including novel metastases to the brain. Furthermore, in collaboration with H-RAS, BMI1 induced fulminant metastatic disease in the lung using a tail vein model of haematogenous spread through accelerated cellular proliferation and inhibition of apoptosis. Finally, we show that knockdown of BMI1 in several established breast cancer cell lines leads to decreased oncogenic behaviour in vitro and in vivo. In summary, BMI1 collaborates with H-RAS to induce an aggressive and metastatic phenotype with the unusual occurrence of brain metastasis, making it an important target for diagnosis and treatment of aggressive breast cancer.