Researchers at the University of California San Diego have discovered a new potential treatment target for triple-negative breast cancer (TNBC), which is known to be the most aggressive form of breast cancer. The study found that a protein called PUF60 plays a critical role in supporting the growth and survival of TNBC cells by regulating how key genes are spliced.
In laboratory models, disrupting PUF60’s activity caused widespread errors in gene processing. This led to DNA damage, cell-cycle arrest, and ultimately the death of tumor cells. Notably, healthy breast cells were not affected when PUF60 was disrupted.
TNBC remains difficult to treat because it does not respond to existing targeted therapies like immunotherapy or hormone therapy. As a result, patients often face poor outcomes. Cancer researchers continue to search for new ways to attack TNBC by targeting the molecular mechanisms that allow cancer cells to survive.
The research team screened over 1,000 RNA-binding proteins in TNBC cells and identified 50 essential for their survival. Among these, PUF60 stood out as a top candidate. Reducing or mutating PUF60 led to significant gene processing errors and tumor cell death in experimental models. In mouse models with TNBC, loss of PUF60 resulted in substantial regression of tumors while leaving healthy breast tissue largely unaffected.
“This study highlights PUF60-mediated RNA splicing as a promising therapeutic angle for TNBC and potentially other cancers characterized by replication stress,” said the authors. “By pinpointing PUF60 as a regulator that cancer cells depend on — but healthy cells do not — the findings suggest a new direction for future drug development.” They noted that further studies will be needed to determine whether inhibitors targeting PUF60 or its interactions can become viable treatments.
The research was published in Cancer Research and led by Corina Antal, Ph.D., assistant professor, and Gene Yeo, Ph.D., professor at UC San Diego School of Medicine. Both are also members of UC San Diego Moores Cancer Center.
