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.
Bibliographical noteFunding Information:
We are grateful to Max Wicha for providing the shRNA lentiviral constructs, George Dunn, Asa Dorsey and Gail McMullen for animal care, Zi-ayo Liu for lentiviral transductions and Suresh Arya for advice on lentiviral preparation, and Aleksandra Michalowski and the NIH Biostatisitics Branch for assistance with statistical analysis. This work was supported in part by the Intramural Program of the NIH, Center for Cancer Research, National Cancer Institute and by RO1CA 094150 (GD).
- Breast cancer
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research