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Searching Cancer Stem-like Cells, Researchers ID miRNA Linked to Breast Cancer Brain Metastasis

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By targeting a subclass of metastatic breast cancer cells called cancer stem-like cells, a team led by researchers at the Southern Illinois University School of Medicine has found a microRNA, miR-7, that appears to play a key role in brain-specific breast cancer metastasis.

The group, led by Southern Illinois' Hiroshi Okuda, and Fei Xing of the University of Mississippi Medical Center, published its results in a study in Cancer Research this week.

Studying metastatic breast cancer cells in vitro and in mouse models, the researchers found that expression of miR-7 was significantly down-regulated in cancer cells that spread to the brain. The team also showed that miR-7 suppresses metastasis to the brain by modulating a gene involved in stem cell formation, KLF4.

Based on the results, the group is optimistic that this miR-7 and KLF4 connection may serve as a useful biomarker and a potential therapeutic target for brain-metastatic breast cancer, "which is almost always incurable at the present time," according to the study authors.

The study's senior author, Kounosuke Watabe, told Gene Silencing News in an email that the team believed that by specifically targeting CSCs — which have been studied for their role in tumor initiation and chemoresistance — it would be more likely to identify a potentially useful biomarker.

"Cancer stem-like cells, also called tumor-initiating cells, have abilities of self-renewal and chemoresistance. Therefore, it is believed that CSCs are, by definition, responsible for metastatic disease. In order to find a therapeutic target it makes sense to identify specific molecules for these cells," he wrote.

In the study, Watabe and his colleagues used microarrays to profile CSCs isolated from three breast cancer cell lines: a parent line and two metastatic variants known to target either bone or brain tissue very selectively.

The researchers extracted RNA from the isolated CSCs, then hybridized the samples to a miRNA chip from LC Science containing 894 human miRNAs. After analyzing the array data, the team narrowed down two molecules, miR-7 and miR-21, which were significantly reduced in both the brain and bone-targeting cell lines compared to the non-targeted line.

Using qPCR to confirm the result, the group found that only miR-7 was significantly down-regulated in the metastatic cell lines. According to the authors, this suggests that "miR-7 has a specific function in metastatic CSCs to brain and bone."

With their focus now on miR-7, the group found that the miRNA was specific to metastatic CSCs over metastatic cells in general in the three cell lines. They then replicated this in another set of cell lines with the same result.

After studying several databases, the group narrowed down potential targets of miR-7 to a gene, KLF4, which is involved in maintenance of stemness in progenitor cells. According to the group, KLF4 has been found to be over-expressed in 70 percent of breast cancers.

The researchers then experimented in vitro to show that by ectopically expressing miR-7, they could suppress the expression of KLF4 in metastatic cell lines. Interestingly, although the early experiments showed that miR-7 and KLF were inversely correlated in both the brain- and the bone-specific CSCs, when the team examined 710 retrospective results from set of clinical cohorts, they found that expression of KLF4 was inversely correlated with brain metastasis-free survival, but not bone metastasis-free survival.

In a follow-up mouse experiment, the group showed that mice injected with brain-targeting CSCs carrying miR-7 showed significantly less tumor activity in their brains than those who received regular CSCs. But when the group replicated the experiment using the bone-targeting metastatic cell line, they did not see the same differentiation.

According to the authors, this brain specificity of miR-7 and KLF4 is "likely due to the downstream targets of this pathway or related to microenvironmental factors of [the] brain."

Finally, the group studied microdissected tumor tissue from a small set of both primary breast cancer and brain metastatic lesions using qRT-PCR. The researchers found that miR-7 expression was significantly lower, and KLF4 expression significantly higher, in the brain metastatic tissue compared with primary tumors.

Overall, the results support miR-7 and its influence on KLF 4 as a potential marker specific to breast cancer that spreads to the brain.

Watabe said in his email that the group is working to extend the study and validate its finding. "We have been identifying microRNAs that are secreted as exosomes from brain metastatic cells … and we are also [exploring] these RNAs by focusing on their clinical utility," he wrote.

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