Premium
The polycomb group protein Bmi‐1 collaborates with H‐Ras to promote cellular proliferation and transformation of mammary epithelial cells in vitro, and development of poorly differentiated mammary tumors in vivo
Author(s) -
Hoenerhoff Mark James,
Datta Syamal,
Dimri Goberdhan P.,
Simpson Mark R.,
Green Jeff E.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a79
Subject(s) - oncogene , cancer research , biology , malignant transformation , cancer , breast cancer , apoptosis , in vitro , cell cycle , genetics
The polycomb group protein Bmi‐1 is a transcription repressor reported to regulate self‐renewal of normal and cancer stem cells, and prevent cellular senescence through inhibition of cyclin‐dependent kinase inhibitors p16 Ink4a and p19 Arf . Originally discovered as a cooperating oncogene with c‐Myc in a murine model of leukemia, overexpression of Bmi‐1 has since been reported in several forms of cancer, including breast cancer. A direct or collaborative role of Bmi‐1 in the pathogenesis of breast cancer would be critical in the development of novel biomarkers for diagnosis and treatment of this disease. Our soft agar assays suggest a collaborative role of Bmi‐1 with H‐Ras in the induction of proliferation, transformation and invasion of mammary epithelial cells (MEC) in vitro. We show that overexpression of Bmi‐1 alone and in combination with H‐Ras in normal MEC (MCF10A) markedly changes cellular morphology, increases proliferative indices, and decreases the apoptotic response to apoptosis‐inducing agents in vitro. By injecting MCF10A cells overexpressing Bmi‐1, H‐Ras or Bmi‐1 and H‐Ras in SCID mice, we show that while Bmi‐1 overexpression alone cannot induce mammary tumors, the combination of Bmi‐1 and H‐Ras induces development of poorly‐differentiated aggressive mammary neoplasms. These findings suggest collaboration between H‐Ras and Bmi‐1 to induce neoplastic transformation of mammary epithelium.