A team of researchers at the University of North Carolina (UNC) and the Lineberger Comprehensive Cancer Center (LCCC) have identified an enzyme that promotes the proliferation of basal-like breast cancers.
Basal-like breast cancers are among the most aggressive forms of breast cancer and can be very difficult to treat. These forms of breast cancer are more common in women under the age of 26 and in women of African descent. Basal-like breast cancers rapidly metastasize to the brain and lung through blood vessels. While some patients have survived more than 10 years following diagnosis, for most patients the prognosis is poor. New methods of treated these aggressive breast cancers are desperately needed.
What is not particularly well understood is what makes basal-like breast cancers so aggressive, which has been a major focus for research.
The UNC/LCCC researchers investigated transcription factors and the mechanisms that regulate them, in particular, a transcription factor known as FOXM1 which is known to be present in large amounts in basal-like breast cancer cells.
Transcription factors control the rate that genetic information is copied from DNA to mRNA in cells and are important for the completion of the cell cycle and cell proliferation.
It was previously known that the transcription factor FOXM1 contributed to cell cycle progression and upregulated basal-like breast cancers, but it was not known how FOXM1 was regulated. The UNC/LCCC researchers believe they have identified one of the driving factors – An enzyme called USP21.
Using a RNA interference-based screening technique, the researchers identified the USP21 enzyme and showed that the more of the enzyme that was present in cells, the more FOXM1 was produced in the cell cycle. USP21 appeared to also increase the stability of FOXM1. By decreasing the amount of USP21, the researchers showed there was a major reduction in proteins associated with the FOXM1 transcription network and they were able to slow down cell cycle progression.
The identification of the enzyme is important as it could serve as a potential target in new therapies for basal-like breast cancers. In addition to developing drugs to inhibit USP21 the researchers have suggested that targeting the enzyme cancer cells could make them become more sensitive to therapies currently being used to treat breast cancer.
“We think it’s possible to develop a drug to inhibit USP21 in the future, to trick the cancer cells into destroying FOXM1 and stopping cancer cells from continuing to grow and proliferate,” said Anthony Arceci, PhD, first author of the paper.
The research is detailed in the paper – FOXM1 Deubiquitination by USP21 Regulates Cell Cycle Progression and Paclitaxel Sensitivity in Basal-like Breast Cancer – which was recently published in the journal Cell Reports. DOI: 10.1016/j.celrep.2019.02.054