Can Metastasis of Triple-Negative Breast Cancer Be Thwarted?

January 24, 2013

Researchers discovered that in triple-negative breast cancer, an inhibitor of metastasis, miR-708, is repressed, results that could lead to novel therapies.

Researchers have demonstrated how a particularly aggressive type of breast cancer, triple-negative disease, spreads to other parts of the body. The results may lead to new therapies that could treat metastatic breast cancer. The findings are published in Cancer Cell.

Triple-negative breast cancer (TNBC) readily spreads to other parts of the body and has few treatment options-there are currently no therapies specifically for TNBC approved by the US Food and Drug Administration. Approximately 15% to 25% of all breast cancers are TNBC.

Researchers at the Weill Cornell Medical College of Cornell University in New York and colleagues have identified a microRNA (miRNA), the small RNA molecules that regulate gene expression, called miR-708 that is repressed in metastatic breast cancer. Expression of the miRNA in breast cancer mouse models specifically blocked metastasis, but did not affect primary tumor growth. The study shows that miR-708 normally functions as a metastatic tumor inhibitor.

“These studies suggest that miR-708 has the potential in the treatment of extraordinarily high-risk breast cancer patients,” said lead study author Vivek Mittal, PhD, associate professor of cell and developmental biology at Weill Cornell Medical College, referring to patients with TNBC whose cancer has metastasized. “TNBC is almost like a death sentence for these patients.”

The study of the miRNA also presents a theory for why TNBC is more malignant compared with other breast cancer types. Using primary and metastatic breast cancer patient tumor samples, Mittal and colleagues showed that miR-708 is present in all types of primary breast tumors, but is not expressed in metastatic breast tumors. However, miR-708 was downregulated (expressed less) in TNBC compared with other breast cancer types. “We think that TNBC is the most metastatic because the primary tumor itself may contain more metastatic, stem-like cells.” Earlier studies have suggested this to be the case.

MiR-708 normally functions to decrease intracellular calcium levels, resulting in activation of the ERK/FAK pathway that impairs the ability of cells to migrate and, therefore, metastasize. When miR-708 is inhibited, the cells can readily migrate and invade other organs. Higher calcium levels trigger migratory pathways that help cancer cells travel to other organs and can lead to metastasis.

When the researchers delivered synthetically made miR-708 to mice with primary TNBC tumors, the miRNA was able to block metastasis development of the TNBC tumor cells in the lungs of the mice.

“The surprising part is that miR-708 does not affect primary tumor growth, but impacts metastasis alone, suggesting its exclusive role in later metastasis pathways,” said Mittal.

The study also identified the protein complex that inhibits expression of miR-708. The complex works to remodel proteins to epigenetically silence certain genes.

“Our finding is significant,” said Mittal. “Since previously discovered breast cancer miRNAs targeted primary tumor growth by affecting proliferation and apoptosis, it was difficult to discern their role following metastatic dissemination.”

According to Mittal, two approaches to target the miR-708 miRNA are ongoing. One is using an epigenetic therapeutic approach by inhibiting one of the complexes that silences miR-708. Another is directly adding back miR-708 miRNA using either liposomes or nanoparticles for delivery.

If targeted agents against miR-708 are developed, they would be among the first that would restore the normal function of an miRNA and the first to specifically target cancer metastasis.

The current study identified miR-708 using a next-generation miRNA sequencing approach. Had a microarray approach been used, the miR-708 miRNA would not have been identified, as it was not available on any of the microarray platforms, said Mittal. “MiRNA sequencing is powerful and allows discovery of known and novel miRNAs.” Whether miR-708 also has a role in metastasis in other cancers has yet to be addressed.