New insights into why tumor suppressor proteins go awry in cancer

By Samantha Black, PhD, ScienceBoard editor in chief

October 23, 2019 -- Researchers from Stowers Institute for Medical Research in Kansas City, MO have identified proteins that are involved in tumor growth and metastasis in many cancers such as breast cancer. The research was published in Science Advances on October 23.

Breast cancer is one of the many types of cancer that can be caused by gene alterations of SMAD4. Nearly 12% of all women in the US develop breast cancer over the course of their lifetime. Potential new treatments may be possible by identifying targets specifically involved in tumor growth. Other cancers affected by SMAD4 include pancreas, colorectal, prostrate. In these cancers, SMAD4 function is normally impaired.

Breast tumor kinase (BRK) is a nonreceptor tyrosine kinase that is highly expressed in most breast cancer cell lines and tumors. BRK is implicated in increased cell proliferation and migration and enhanced tumor formation.

"The BRK kinase is present in more than 85 percent of breast cancer tumors," said Sayem Miah, PhD, a postdoctoral research associate in the laboratory of Michael Washburn, PhD, at the Stowers Institute. "Our research suggests that treatments targeting BRK may help keep SMAD4 function intact, therefore reducing or stopping tumor growth," Miah says.

The researchers used a kinome array to understand how BRK regulates signal transduction of the transforming growth factor (TGF-b1)//SMAD signaling pathway and they identified SMAD4 as a potential BRK target. Interestingly, SMAD4 is one of the most commonly mutated genes in cancers. SMAD4 is a transcription factor protein that is normally involved in the regulation of cell growth processes.

Miah began this research while he was a PhD student at the University of Saskatchewan, Saskatoon, Canada. "We've known for a while that BRK functions like an oncogene - a gene that has the potential to cause cancer when mutated or abnormally expressed - in breast cancer," Miah explains. "Ultimately, we want to know whether BRK alone can drive breast cancer progression, and if so, by what mechanism."

With a series of immunological, biochemical, genomics, and proteomics approaches, the team provided evidence that BRK regulates TGF-b1/SMAD signal transduction pathway in cancer and normal cells. The team found that BRK competitively binds and phosphorylates SMAD4 and regulates the pathway. The newly phosphorylated SMAD4 is a target of ubiquitin ligases and is subsequently degraded through the ubiquitin-proteasome system leading to tumor growth. The evidence suggests that BRK signaling may be a new target for the treatment of SMAD4-repressed cancers.

The authors believe that the findings of this work are an important step towards understanding how cancer works. They would like to find additional molecules that work with BRK to degrade SMAD4. "If we can further increase our understanding of this protein network, these insights may reveal new targets for metastatic cancer intervention," said Miah.

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