“We wanted to identify microRNAs 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,” says Francesco Nicassio, a principal investigator and Center Coordinator of the Center for Genomic Science at the Italian Institute of Technology in Milan.

In the new study, Nicassio and colleagues, including co-senior author Pier Paolo Di Fiore, a group leader at the European Institute of Oncology and professor at the University of Milan, identified two closely related microRNAs, miR-146a and miR-146b, that are present in breast cancer stem cells as well as normal mammary stem cells. Indeed, the levels of these two microRNAs tended to be highly elevated in aggressive breast cancers that have a high number of cancer stem cells and a poor prognosis.

The researchers found that miR-146a/b are required to maintain the pool of cancer stem cells. Depleting these two microRNAs from patient-derived cancer cells reduced the ability of these cells to form new tumors when implanted into mice.

Nicassio and colleagues determined that miR-146a/b regulate hundreds of messenger RNAs, thereby controlling numerous cellular processes such as metabolism and DNA replication. Depleting miR-146a/b from cancer stem cells might alter these processes in ways that leave the cells more vulnerable to chemotherapy. Nicassio and colleagues found that reducing the levels of miR-146a/b made breast cancer stem cells over 20 times more sensitive to methotrexate, significantly improving this metabolic inhibitor’s ability to restrict tumor growth in mice.

“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.

Source: Eurekalert