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Bmi-1 Cooperates with H-Ras to Transform Human Mammary Epithelial Cells via Dysregulation of Multiple Growth-Regulatory Pathways

¹ Division of Cancer Biology and Department of Medicine, ENH Research Institute, and ² Division of Molecular Oncology and ³ Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Evanston, Illinois; and ⁴ Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Goberdhan P. Dimri, ENH Research Institute, 1001 University Place, Evanston, IL 60201. Phone: 224-364-7521; Fax: 224-364-7402; E-mail: g-dimri{at}northwestern.edu or Jeffrey E. Green, Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892. Phone: 301-435-5193; Fax: 301-496-8709; E-mail: jegreen{at}nih.gov.

Elevated expression of Bmi-1 is associated with many cancers, including breast cancer. Here, we examined the oncogenic potential of Bmi-1 in MCF10A cells, a spontaneously immortalized, nontransformed strain of human mammary epithelial cells (HMEC). Bmi-1 overexpression alone in MCF10A cells did not result in oncogenic transformation. However, Bmi-1 co-overexpression with activated H-Ras (RasG12V) resulted in efficient transformation of MCF10A cells in vitro. Although early-passage H-Ras–expressing MCF10A cells were not transformed, late-passage H-Ras–expressing cells exhibited features of transformation in vitro. Early- and late-passage H-Ras–expressing cells also differed in levels of expression of H-Ras and Ki-67, a marker of proliferation. Subsets of early-passage H-Ras–expressing cells exhibited high Ras expression and were negative for Ki-67, whereas most late-passage H-Ras–expressing cells expressed low levels of Ras and were Ki-67 positive. Injection of late-passage H-Ras–expressing cells in severe combined immunodeficient mice formed carcinomas with leiomatous, hemangiomatous, and mast cell components; these tumors were quite distinct from those induced by late-passage cells co-overexpressing Bmi-1 and H-Ras, which formed poorly differentiated carcinomas with spindle cell features. Bmi-1 and H-Ras co-overexpression in MCF10A cells also induced features of epithelial-to-mesenchymal transition. Importantly, Bmi-1 inhibited senescence and permitted proliferation of cells expressing high levels of Ras. Examination of various growth-regulatory pathways suggested that Bmi-1 overexpression together with H-Ras promotes HMEC transformation and breast oncogenesis by deregulation of multiple growth-regulatory pathways by p16^INK4a-independent mechanisms. [Cancer Res 2007;67(21):10286–95]