MicroRNAs Essential to Survival of Breast Cancer Stem Cells Could be Targeted to Improve Success of Chemotherapy

MicroRNAs Essential to Survival of Breast Cancer Stem Cells Could be Targeted to Improve Success of Chemotherapy

Two microRNA molecules have been identified that play an important role in the maintenance of populations of cancerous stem cells that drive breast cancer growth and lead to relapse after treatment.

While tumors can be targeted with radio and chemotherapies, most tumors also contain a small population of cancer stem cells that cause tumors to reform after treatment. These cancer stem cells are often resistant to radio and chemotherapies, which is why many patients relapse after treatment and have new tumors form. The cancer stem cells can also promote metastasis after the initial treatment, making the prognosis for patients poor.

Patients with breast cancer that have high numbers of cancer stem cells typically have a poorer prognosis than those with tumors that contain relatively low numbers of cancer stem cells. The key to successful treatment is to ensure that the cancer stem cells are also killed.

MicroRNAs are believed to play a role in ensuring the survival of cancer stem cells. MicroRNAs are short RNA molecules that control the fate and identity of cells through the regulation of the levels of protein-encoding messenger RNAs. MicroRNAs are essential for maintaining normal stem cells that are inherited by cancer stem cells, and these microRNAs could potentially be targeted in new therapies for cancers such as breast cancer. If microRNA activity essential to the survival of cancer stem cells could be disrupted, the prognosis for breast cancer patients could be greatly improved.

The Italian researchers identified two such microRNA molecules – miR-146a and miR-146b – that are present in breast cancer stem cells as well as normal mammary stem cells. Both of these microRNAs were found at highly elevated levels in aggressive breast cancers, those that have high levels of cancer stem cells and are often fatal. Both of these MicroRNAs are closely related and are critical for maintaining the pool of cancer stem cells in breast cancer.

The researchers found that when both of these microRNAs were depleted in patient-derived cancer cells, they had a much lower ability to form new tumors when they were transplanted into mice.

The researchers found that these two microRNAs were involved in the regulation of hundreds of messenger RNAs and therefore played a critical role in several cellular processes, including metabolism and DNA replication. They suggest depleting levels of these microRNAs could make cells much more susceptible to chemotherapy. In their study, they found that reducing the levels of both of these microRNAs made breast cancer stem cells 20 times more sensitive to the chemotherapy drug methotrexate.

“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,” said Francesco Nicassio, principal investigator and Center Coordinator of the Center for Genomic Science at the Italian Institute of Technology in Milan.

You can read more about the study in the paper – miR-146 connects stem cell identity with metabolism and pharmacological resistance in breast cancer– which was recently published in the Journal of Cell Biology. DOI: 10.1083/jcb.202009053