Bmi-1 Cooperates with H-Ras to Transform Human Mammary Epithelial Cells via Dysregulation of Multiple Growth-Regulatory Pathways
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- Sonal Datta
- 1Division of Cancer Biology and Department of Medicine, ENH Research Institute, and
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- Mark J. Hoenerhoff
- 4Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland
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- Prashant Bommi
- 1Division of Cancer Biology and Department of Medicine, ENH Research Institute, and
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- Rachana Sainger
- 1Division of Cancer Biology and Department of Medicine, ENH Research Institute, and
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- Wei-Jian Guo
- 1Division of Cancer Biology and Department of Medicine, ENH Research Institute, and
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- Manjari Dimri
- 2Division of Molecular Oncology and
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- Hamid Band
- 2Division of Molecular Oncology and
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- Vimla Band
- 1Division of Cancer Biology and Department of Medicine, ENH Research Institute, and
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- Jeffrey E. Green
- 4Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland
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- Goberdhan P. Dimri
- 1Division of Cancer Biology and Department of Medicine, ENH Research Institute, and
抄録
<jats:title>Abstract</jats:title> <jats:p>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 p16INK4a-independent mechanisms. [Cancer Res 2007;67(21):10286–95]</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 67 (21), 10286-10295, 2007-11-01
American Association for Cancer Research (AACR)