Breast Cancer Metastasis into the Brain Depends on a Specific MicroRNA

The ability of breast cancer cells to spread into the brain is controlled by the regulation of the gene KLF4 (Krueppel-like factor 4) by the microRNA (miRNA) miR-7.

Despite significant improvement in survival rates of patients with breast cancer, prognosis of metastatic disease is still bleak. While cancer stem-like cells (CSC) are considered to play a role in the spread of breast cancer, the exact pathologic role of CSCs has not yet been elucidated.

To better understand the molecular mechanisms that drive breast cancer metastasis investigators at the University of Mississippi Medical Center (Jackson, USA) performed microRNA (miRNA) profile analyses on CSCs isolated from metastatic breast cancer cell lines. MiRNAs are molecular fragments of about 20 nucleotides that block gene expression by attaching to molecules of messenger RNA (mRNA) in a fashion that prevents them from transmitting the protein synthesizing instructions they had received from the DNA.

The investigators reported in the February 5, 2013, online edition of the journal Cancer Research that CSCs isolated from metastatic breast cell lines were significantly more metastatic than non-CSC populations in an organ-specific manner. The results of the miRNA profile analysis for these cells revealed that CSCs that were highly metastatic to bone and brain expressed significantly lower levels of miR-7 and that this miRNA was capable of modulating one of the essential genes for induced pluripotent stem cells, KLF4 (Krueppel-like factor 4).

High expression of KLF4 was significantly and inversely correlated to brain but not bone metastasis-free survival of patients with breast cancer, and the expression of miR-7 significantly suppressed the ability of CSCs to metastasize to brain but not to bone in an animal model. In addition, the expression of miR-7 and KLF4 were significantly down- or upregulated, respectively, in the tumor cells in brain metastatic lesions obtained from human patients.

“Recent research has shown that microRNAs are involved in tumor initiation and progression, and we hypothesized that they also may play a role in metastasis, particularly in relation to cancer stem-like cells,” said senior author Dr. Kounosuke Watabe, professor of microbiology and biochemistry at the University of Mississippi Medical Center. “We found that miR-7 is a metastasis suppressor in cancer stem-like cells,” said Dr. Watabe. “When we increased expression of miR-7 in cancer stem-like cells from metastatic human breast cancer cell lines, it suppressed their metastatic properties. High expression of KLF4 was inversely associated with brain metastasis-free survival but was not associated with bone metastasis. This was confirmed in an animal model when we found that expression of miR-7 significantly suppressed the ability of cancer stem-like cells to metastasize to the brain but not the bone. Cancer cells find the brain to be a kind of sanctuary where they can survive longer. It is possible that miR-7 and KLF4 may serve as diagnostic or prognostic markers, or therapeutic targets for the prediction of, or treatment of, brain metastasis.”

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