microRNAs Boost Breast Cancer Growth and Drive Therapy Resistance

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Two micro (mi)RNAs – miR-146a and miR-146b — are present at high levels in breast cancer stem cells and appear to drive their renewal and boost tumor growth, show results from an Italian study.

Notably, the researchers found that resistance to anti-folate chemotherapies was common in breast cancer stem cell populations, but that removal of miR-146a or b seemed to reverse this resistance.

“Cancer stem cells lie at the apex of the hierarchical cellular organization of different types of solid tumors and are thought to drive tumor initiation, therapy resistance, relapse, and metastasis,” write Francesco Nicassio, Ph.D., a senior researcher at the Center for Genomic Science at the Italian Institute of Technology in Milan and colleagues in the Journal of Cell Biology.

This process can be problematic for oncologists, as if a few of these cells remain in cancerous tissue it can trigger recurrence even if the cancer has seemingly been treated successfully. Indeed, breast cancer patients with high levels of cancer stem cells have a poorer prognosis than those with lower levels.

The fine detail of how these stem cells drive tumor growth and build therapy resistance is still not fully understood. One route could be through miRNAs. These small regulatory RNAs help drive gene expression and cell fate by regulating messenger(m) RNA, which translates genes into proteins.

To investigate the role of miRNAs in breast cancer, Nicassio and team measured the levels of miR-146a and b in samples from normal breast tissue and cancerous tissue from humans and a mouse model.

“We wanted to identify miRNAs required for the maintenance of normal mammary stem cells that are inherited by cancer stem cells and could represent potential therapeutic targets in breast cancer,” explained Nicassio.

The scientists found miR-146a and b were present in both normal mammary stem cells and in cancer stem cells. But they were present in significantly higher numbers in the cancer stem cells, particularly in more aggressive breast cancers. Loss of miR-146 seemed to reduce the ability of the cancer stem cells to renew themselves and decrease the number of cancer initiating cells.

When the team experimented with reducing levels of miR-146 in a mouse model of breast cancer they found the cells became much (20 times) more sensitive to methotrexate than before.

A transcriptional analysis of miR-146 showed it interacts and plays a role in multiple physiological processes including metabolism, RNA transcription and DNA synthesis and repair.

“While the molecular details remain to be determined, our results clearly show that reducing miR-146a/b levels represents an attractive approach to overcome some forms of drug resistance in the clinical setting, unmasking a ‘hidden vulnerability’ exploitable for the development of anti-cancer stem cell therapies,” Nicassio says.

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