BMI1 and H-RAS Cooperate to Drive Breast Cancer Metastasis

image of cells

Graphic shows two groups of mice getting injected, each with a different kind of mammary epithelial cells. One group of cells has H-RAS highly expressed, and the other has both H-RAS and BMI highly expressed. H-RAS alone produced 50 percent of mice with liver metatases, 40 percent with spleen mets, and 0 percent with brain mets. Group receiving cells with H-RAS plus BMI highly expressed, produced 100 percent of the mice with both liver and spleen mets, and 30 percent of mice with mets to the brain. When the same duet of altered mammary cells were injected into the blood stream of the mice, both groups of mice developed lung mets, but tumors were much larger in the mice who received cells with high expression of both H-RAS and BMI.

There have been significant improvements in the diagnosis of breast cancer at early stages of the disease. However, even when patients are identified early, there is a 30 percent chance of recurrence after apparently successful treatment of the initial tumor. The major cause of death for breast cancer patients is metastasis of the tumor to other organs but, unfortunately, the mechanisms of metastatic progression and cancer recurrence are poorly understood.

Overexpression of the protein BMI1 correlates with poor prognosis in several human cancers and is associated with an increased risk of metastasis. BMI1 is a transcription repressor that regulates genes by inhibiting their expression by modifying chromatin structure. Under normal circumstances, BMI1 participates in the maintenance of stem cells and their self-renewal by modulating the expression of tumor suppressors that reduce cell growth.

Mark Hoenerhoff, D.V.M., Ph.D., as a postdoctoral fellow in the laboratory of Jeff Green, M.D., chief of the Transgenic Oncogenesis and Genomics Section, CCR Laboratory of Cancer Biology and Genetics, studied the role of BMI1 in cancer progression and role in metastasis using a combination of human gene expression studies and mouse models. Dr. Hoenerhoff and his colleagues recently published a study in Oncogene demonstrating that BMI1 cooperates with a another oncogene, H-RAS, to promote an aggressive and metastatic form of breast cancer.

When cells undergo oncogenic transformation, they often exhibit an increase in growth rate, a decrease in programmed cell death (apoptosis) in response to DNA damage, and an increase in the ability to invade neighboring tissue. Overexpression of either BMI1 or H-RAS caused cultured human mammary epithelial cells to acquire all three of these characteristics. When the cells expressed both proteins, these properties were further enhanced. Depletion of BMI1 reversed these trends in several cases, which indicates that BMI1 can be an important regulator of aggressive behavior in mammary oncogenesis.

The researchers also found in vivo evidence of cooperation between BMI1 and H-RAS. Implantation of human mammary epithelial cells overexpressing H-RAS into mice resulted in liver and spleen metastasis in approximately half of the animals; the additional overexpression of BMI1 resulted in metastases in all of the animals. It was also determined that a subset of mice overexpressing both BMI1 and H-RAS developed metastasis in the brain. The incidence of brain metastasis was an especially significant result because the brain is a common location for breast cancer metastasis, but spontaneous mammary cancer metastasis to the brain is very difficult to model in laboratory animals.

Further evidence of a link between BMI1 and H-RAS was discovered when human mammary epithelial cells were injected into the bloodstream of mice to simulate metastatic spread to the lungs. The cells overexpressing both BMI1 and H-RAS quickly formed aggressive tumors in the lungs. However, cells only overexpressing H-RAS developed much smaller lung lesions after a significantly longer period of time. This difference was that the aggressive tumors acquired a survival advantage resulting from BMI1 overexpression, which lead to a decrease in apoptosis and an increase in proliferation.

The ability of BMI1 and H-RAS to cooperatively induce an aggressive and metastatic form of breast cancer suggests that these molecules may be important targets for treatment of this disease. The development of this mouse model of breast cancer metastasis to the brain should lead to a better understanding of the processes that contribute to breast cancer mortality and facilitate the development of interventions to improve outcomes of these patients.

Summary Posted: 08/2009

Reference

Hoenerhoff MJ, Chu I, Barkan D, Liu ZY, Datta S, Dimri GP, Green JE. BMI1 cooperates with H-RAS to induce an aggressive breast cancer phenotype with brain metastases. Oncogene. 2009 Aug 27;28(34):3022-32. PubMed Link