BMI1 cooperates with H-RAS to induce an aggressive breast cancer phenotype with brain metastases

Abstract

BMI1 is a member of the polycomb group of transcription repressors that functions in stem cell maintenance and oncogenesis through 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 via dysregulation of multiple growth pathways independent of the INK4A/ARF locus. In this study, we demonstrate 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.

A Positive Feedback Loop Regulates the Expression of Polycomb Group Protein BMI1 via WNT Signaling Pathway

“…The primary mechanism by which PcG proteins promote oncogenesis and metastasis appears to be by senescence bypass (18,19) and increased cell survival (3,6). The exact mechanism by which BMI1 exhibits oncogenic activity is not known.…”

“…We also determined the expression of WNT1, Myc, and DKK1 in an MCF10A tumor progression series consisting of MCF10A-B0 (normal immortal), MCF10A-BMI1 (epithelial to mesenchymal transition-positive and partially transformed), MCF10A-Ras (transformed), and MCF10A-BMI1ϩRas (transformed, aggressive, and metastatic) (5,6). Our data showed an increased expression of WNT1 and c-Myc and correspondingly decreased expression of DKK1, which correlated with an aggressive phenotype of the cells (Fig.…”

“…In particular, BMI1 and EZH2 are known to be overexpressed in a number of human malignancies including breast and prostate cancers (2)(3)(4). In vitro models of cancer development strongly support an oncogenic role of overexpressed BMI1 in cancer and metastasis (5,6). In addition to its role in cancer, BMI1 is known to be required for self-renewal of neural, hematopoietic, intestinal, and mammary stem cells (7)(8)(9)(10)(11)(12).…”

A feedback loop that regulates the expression of polycomb group protein Suz12 via non-canonical WNT signaling pathway in blast crisis of chronic myeloid leukemia

“…These proteins are often aberrantly expressed in cancer cells and, in particular, Suz12, EZH2 and BMI1 are well known to be over-expressed in a certain number of human tumors including breast cancer, prostate cancer and chronic myeloid leukemia [5,6,9,10,15,20]. The principal mechanism by which PcG proteins promote tumorigenesis and metastasis seems to be senescence bypass [1,8] and increase cell survival [6,7]. Recent studies have shown that PcG proteins may also regulate cellular and oncogenic functions in a transcription repression-independent manner.…”

BMI-1 is important in bufalin-induced apoptosis of K562 cells

“…However, various studies suggest that BMI-1 may be an important collaborating factor in the transformation process. For example, BMI-1 is able to cooperate with H-RAS to induce aggressive breast cancer with brain metastases (70,71). Using qPCR, Merkerova et al (72) demonstrated significantly increased levels of BMI-1 transcripts in chronic myelogenous leukemia (CML) cells.…”