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

Abstract

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 earlypassage 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 latepassage 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]

The cell cycle regulator ecdysoneless cooperates with H-Ras to promote oncogenic transformation of human mammary epithelial cells

“…9 We have previously shown that normal or immortal hMECs do not exhibit anchorage independence, while their oncogenically-transformed derivatives do. 10 Consistent with previous findings, vector control 76N. TERT cells showed few smaller colonies when plated on soft agar ( Fig.…”

“…Ras activation provides a major branch of signaling to link ErbB2 oncogene to cell cycle progression, and mutant H-Ras is very commonly used in cooperative oncogenesis protocols to transform hMECs. 10,30 Therefore, we used retroviral infection to stably overexpress Ecd and/or H-RasQ61L in hTERT-immortalized but non-tumorigenic hMEC line 76N.TERT that is strictly dependent on exogenous growth factors for cell cycle progression and proliferation. 7,8 Western blot analysis of cell lysates confirmed the expression of overexpressed Ecd and/or Ras in respective single or double transductants ( Fig.…”

Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14ARF-MDM2-p53 axis

“…93 Similar to TWIST1, the BMI1 oncoprotein inhibits oncogene-induced premature senescence and cooperates with activated H-Ras to induce neoplastic transformation and epithelial-mesenchymal transition. 84,94 Thus, both the TWIST1 and BMI1 transcriptional regulators may overcome several oncogene-induced failsafe barriers and may serve as examples of corrupt exploitation of normal developmental programs by tumor cells.…”

Expression of aldehyde dehydrogenase 1 (ALDH1) is associated with basal-like markers and features of aggressive tumours in African breast cancer

“…Still, BMI-1 has been linked to mammary carcinogenesis in some previous studies (Dimri et al, 2002;Datta et al, 2007). Although some find BMI-1 expression to be associated with a favourable prognosis (Kim et al, 2004;Arnes et al, 2008;Choi et al, 2009), others have reported the opposite (Glinsky et al, 2005;Silva et al, 2007).…”