Research alert: New vulnerability identified in aggressive breast cancer

Researchers at University of California San Diego have identified a previously unrecognized treatment target for triple‑negative breast cancer (TNBC), the most aggressive subtype of breast cancer. Their new study reveals that a protein called PUF60 plays an essential role in helping TNBC cells grow and survive by controlling how key genes are spliced. In models of TNBC, disrupting the activity of PUF60 caused widespread errors in gene processing, resulting in DNA damage, cell‑cycle arrest and ultimately tumor cell death. However, healthy cells were unaffected.

TNBC is widely recognized as the most difficult breast cancer to treat because it is very aggressive and does not respond to targeted therapies, such as immunotherapy or hormone therapy, that can be used in other subtypes. Because of this lack of targeted therapies, patients of TNBC often face poor prognosis. To address this gap in available treatments, cancer researchers are working to identify new ways to target this elusive cancer, such as by attacking the molecular machinery cancer cells use to stay alive.

Key findings from the new study include:

• By screening more than 1,000 RNA‑binding proteins in TNBC cells, the researchers identified 50 that are essential to TNBC survival, with PUF60 emerging as a top candidate.
• Knocking down PUF60 — or introducing a precise mutation that disrupts its activity — caused significant DNA processing errors and led to cell death in TNBC models.
• In multiple mouse models of TNBC, loss of PUF60 led to substantial tumor regression.
• Healthy breast cells were largely unaffected by PUF60 loss.

This study highlights PUF60‑mediated RNA splicing as a promising therapeutic angle for TNBC and potentially other cancers characterized by replication stress. 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. However, further research is needed to explore whether inhibitors targeting PUF60 or its splice‑site interactions can be developed as targeted cancer therapies.

The study, published in Cancer Research, was led by Corina Antal, PhD, assistant professor, and Gene Yeo, PhD, professor, both at UC San Diego School of Medicine. Both are also members of UC San Diego Moores Cancer Center.