This chain of events, the scientists found, promotes Herceptin resistance in breast cancer and activation of glucose metabolism (glycolysis), which cancer cells primarily rely on to fuel their growth and survive.
Their research focused on Skp2 E3 ligase, a protein that binds to and tags other proteins with molecules called ubiquitins, in this case to activate the Akt kinase.
"We discovered a novel function of Skp2 E3 ligase that makes it an important player in cancer development and also identified a crucial role for it as a regulator of the glycolysis pathway," said senior author Hui-Kuan Lin, Ph.D., associate professor in MD Andersons Department of Molecular and Cellular Oncology.
"This is potentially important for understanding and addressing Herceptin resistance in breast cancer," Lin said. "The effect on glucose metabolism also could have implications for other types of solid tumor cancers, including prostate, because they rely so heavily on glycolysis."
The team also found that Skp2 overexpression is associated with poor prognosis for breast cancer patients and its spread to other organs.
Lin and colleagues are studying potential inhibitors of Skp2 that might be developed for treatment.
The EGFR family of proteins includes HER2, which abundantly coats cancer cells in about a third of breast cancers, making these tumors prime targets for the targeted drug Herceptin.
Fundamental discovery about Akt activation
The Akt kinase relays signals by growth factors from outside of the cell into the cell. It regulates cell profliferation and survival, metabolism and tumor development, the authors noted.
To do its work, whether normal or oncogenic signaling, it must move from the cytosol to the plasma membrane. To do that, Lin and colleagues had previously shown that Akt must be ubiquitinated – and those ubiquitins must be attached in a specific chain formation, the K63-linked polyubiquitin chains.