Researchers at the University of California San Diego have identified the PUF60 protein as a potential new therapeutic target for triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer. The protein was found to be essential for the growth and survival of TNBC cells by regulating gene splicing, and its disruption led to tumor regression in preclinical models while largely sparing healthy cells.
Introduction
Researchers at the University of California San Diego have identified the PUF60 protein as a previously unrecognized treatment target for triple-negative breast cancer (TNBC). TNBC is the most aggressive subtype of breast cancer, characterized by its rapid progression and limited treatment options.
Understanding Triple-Negative Breast Cancer
Triple-negative breast cancer is considered challenging to treat due to its aggressive nature and its unresponsiveness to targeted therapies, such as immunotherapy or hormone therapy, which are effective for other breast cancer subtypes. This often leads to a poor prognosis for patients. Consequently, cancer researchers are investigating new methods to target this cancer by focusing on the molecular mechanisms cancer cells use for survival.
Key Research Findings
The study identified PUF60 as critical for TNBC cell viability:
- A screening of over 1,000 RNA-binding proteins in TNBC cells identified 50 as essential for TNBC survival, with PUF60 emerging as a primary candidate.
- The PUF60 protein was found to be crucial for the growth and survival of TNBC cells through its role in regulating gene splicing, which influences how key genes are processed.
- Disrupting PUF60 activity, either by reducing its levels (knockdown) or introducing a precise genetic mutation, resulted in widespread DNA processing errors. These errors subsequently led to cell-cycle arrest and cell death in TNBC models.
- In multiple mouse models of TNBC, the loss of PUF60 led to substantial tumor regression.
- Healthy breast cells were largely unaffected by the disruption of PUF60.
Implications for Future Treatment
The findings suggest that PUF60-mediated RNA splicing could represent a promising therapeutic avenue for TNBC and potentially other cancers characterized by replication stress. Identifying PUF60 as a regulator that cancer cells depend on, but healthy cells do not, indicates a new direction for future drug development. Further research is required to determine if inhibitors targeting PUF60 or its splice-site interactions can be developed into targeted cancer therapies.
Study Details
The research was published in the journal Cancer Research. The study was led by Corina Antal, PhD, and Gene Yeo, PhD, both affiliated with UC San Diego School of Medicine and members of UC San Diego Moores Cancer Center.