The development of metastatic beast cancer is considered a leading cause of cancer mortality among women. Years after the removal of the primary breast tumor, metastatic recurrence can occur. Now, for the first time, researchers at the University of California (UC) San Diego, have identified an enzyme that controls the spread of breast cancer. The findings, reported in the September 4, 2014 online edition of the Proceedings of the National Academy of Science (PNAS), offer hope for the leading cause of breast cancer mortality worldwide. According to the American cancer Society, an estimated 40,000 women in the United States will die of breast cancer in 2014.
Commenting on the study, lead author Xuefeng Wu, PhD, a postdoctoral researcher at UC San Diego, noted: “The take-home message of the study is that we have found a way to target breast cancer metastasis through a pathway regulated by an enzyme.”
…primary tumors are not normally lethal… the real danger is caused by cancer cells that have successfully left the primary site, escaped through the blood vessels and invaded new organs…
Regulating cell growth
The enzyme, called UBC13, an E2 enzyme that catalyzes K63-linked protein polyubiquitination, was found to be present in breast cancer cells at two to three times the levels of normal healthy cells. The ubiquitin-conjugating enzyme Ubc13 is required for growth factor ? orTGF?-induced non-SMAD signaling via TAK1 and p38. This is a pathway that is first activated in the primary tumor. Hence, while the enzyme’s role in regulating normal cell growth and healthy immune system function is well-documented, the study is among the first to show a link to the spread of breast cancer.
Specifically, Wu and colleagues with the UC San Diego Moores Cancer Center found that the enzyme regulates cancer cells’ ability to transmit signals that stimulate cell growth and survival by regulating the activity of a protein called p38 which when “knocked down” prevents metastasis.
Of clinical note, the researchers concluded that a compound that inhibits the activation of p38 is already being tested for treatment of rheumatoid arthritis.
Silencing UBC13 and p38
In their experiments, scientists took human breast cancer cell lines and used a lentivirus to silence the expression of both the UBC13 and p38 proteins. These altered cancer cells were then injected into the mammary tissues of mice. Although the primary tumors grew in these mice, their cancers did not spread.
“Primary tumors are not normally lethal,” Wu explained. “The real danger is cancer cells that have successfully left the primary site, escaped through the blood vessels and invaded new organs. It may be only a few cells that escape, but they are aggressive. Our study shows we may be able to block these cells and save lives.”
Researchers have also defined a metastasis gene signature that can be used to evaluate clinical responses to cancer therapies that target the metastasis pathway.
For more information:
Wu X, Zhanga W, Font-Burgadaa J, Palmerb T, Hamile AS, Biswasf SK, et al. Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade. PNAS Sep 4, 2014, doi: 10.1073/pnas.1414358111 [Article]
Photo: A tumor with reduced levels of enzyme UBC13 (top) and a control tumor (bottom) that has spread to the lungs. Photo Courtesy: UC San Diego School of Medicine.
