Small RNA Molecules Block Breast Cancer from Spreading via Newly Identified Secreted Factor

19
May

The role of genes and proteins in cancer control is well known, but now researchers at Jefferson’s Kimmel Cancer Center have found a cluster of microRNA (miRNA) molecules that act to suppress the invasive spread of breast cancer.

MiRNAs are non-coding small RNA molecules found in wide areas of the genome that, either singly or in clusters, regulates gene expression. Links between dysfunctional miRNA and human disease have only recently been made.

In the April 19 online early edition of the Proceedings of the National Academy of Sciences (PNAS), the researchers say that this miRNA cluster (dubbed 17/20) is able to inhibit the ability of breast cancer cells to secrete chemicals that alters the microenvironment surrounding the cells, allowing them to eventually break free, travel and spread. They identified these chemicals and showed they are key to breast cancer spread.

“This is the first evidence of suppression of breast cancer cell migration, invasion, and metastasis by miRNA through regulation of factors secreted by the cancer cells,” says the study’s first author Zuoren Yu, Ph.D., assistant professor of Cancer Biology at Jefferson Medical College of Thomas Jefferson University.

“Previous studies have implicated miRNA in cancer, but being within the cell, they are hard to target as a cancer therapy. By demonstrating the miRNA work via secreted factors, and identifying these factors, the findings bring us closer to novel, rational anti-metastasis therapy for breast cancer,” says the study’s lead investigator, Richard Pestell, M.D., Ph.D., Director of the Kimmel Cancer Center at Jefferson. “Metastatic breast cancer occurs in 20 to 30 percent of women with breast cancer and although traditional treatment therapies may slow down tumor growth, metastatic breast cancer still has a poor survival.”

Pestell, Yu, and their Kimmel Cancer Center team have already shown that miRNA 17/20 is often missing or substantially reduced in breast cancer patients’ tumor biopsies, when compared to cancer free tissue samples. Their prior studies have revealed that the cluster inhibits the cyclin D1 oncogene. Over a decade ago, Pestell’s laboratory was the first to show that cyclin D1 has a critical role in promoting breast tumor growth in animals. “Our research and that of other laboratories are consistent with a growing understanding that miRNA functions as tissue specific tumor suppressor,” Dr. Yu says. “MiRNA 17/20 acts as a tumor suppressor in breast cancer.”

In this study, the researchers found that this miRNA cluster has the added function of decreasing migration, invasion, and metastasis. “We know that one microRNA or a single miRNA cluster can have effects on many genes, and in this case, it seems to be regulating the microenvironment of cancer cells, decreasing the release of growth factors from cancer cells that can lead to cell migration.”

The researchers then delivered extra miRNA 17/20 clusters to laboratory breast cancer cells and found this over-expression blocked key signals that would have allowed cells to detach from each other.

“We found a pathway of cross-talking between cancer cells mediated by miRNA,” Dr. Yu says. “This sheds light on the importance of cell microenvironment for cancer invasiveness and metastasis.”

The researchers are now planning to test the effect of delivering miRNA 17/20 clusters to animal models of human breast cancer.

The work was supported by grants from the National Cancer Institute, the Marian C. Falk Medical Research Trust and the Pennsylvania Department of Health. The authors declare no conflicts of interest.