New approach to triple-negative breast cancer targets tumor-driving RNA proteins

RNA-binding proteins play an important role in the body, helping to control cell growth and translate RNA into different proteins. But when they malfunction, they can fuel cancer. Now researchers from the University of California, San Diego (UCSD) School of Medicine have found one RNA-binding protein that they believe could be targeted in one of the toughest cancers to treat: triple-negative breast cancer.

The UCSD team discovered that an RNA-binding protein called YTHDF2 drives the growth of triple-negative breast tumors. When they removed YTHDF2 from human breast tumors that had been transplanted into mice, the tumors shrank tenfold, they reported in the journal Molecular Cell.

The researchers started by using the CRISPR gene-editing technology to silence RNA-binding proteins in human breast cells that had been engineered to be vulnerable to tumor formation. They found that inhibiting 57 of the proteins killed the cancer cells. Of those, YTHDF2 looked particularly promising.

They went on to use a laboratory technique they developed to study in detail how all the cells in breast tumors behave without YTHDF2. They discovered that cancer cells that lacked the protein were dying from stress-induced programmed cell death, or apoptosis, they reported.

The UCSD team wanted to test the safety of inhibiting YTHDF2, so they engineered mice that lacked the protein in all of the cells in their bodies. The mice appeared completely normal and did not have tumors, they reported, suggesting that normal cells would likely not be affected by a treatment designed to block YTHDF2.

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Triple-negative breast cancer is typically aggressive and resistant to standard therapies. So researchers are hunting for new treatment approaches. Last month, for example, Georgetown University researchers reported their discovery that the AIB1-Delta4 protein drives the metastasis of triple-negative breast cancer cells.

RNA-binding proteins have also generated some interest in the oncology-research community. Massachusetts Institute of Technology researchers created "DNA circuits" that carry genetic instructions for various therapeutic proteins, as well as RNA-binding proteins that could be turned on and off with drugs. Their idea is to control the interaction between RNA and RNA-binding proteins to create an immune response to cancer.

The UCSD team is optimistic but has more preclinical work ahead on RNA-binding proteins, said senior author Gene Yeo, Ph.D., professor of cellular and molecular medicine, in a statement. “We're not yet sure how easily druggable they are in this context, but we've built a solid framework to begin exploring them,” he said.