A protein that fuels an inflammatory pathway does not turn off in breast cancer, resulting in an increase in cancer stem cells, according to new research. This provides a potential target for treating triple-negative breast cancer, the most aggressive form of the disease.
The researchers, from the University of Michigan (U-M) Comprehensive Cancer Center in Ann Arbor and Georgia Regents University in Augusta, identified a protein, SOCS3, which is highly expressed in normal cells but undetectable in triple-negative breast cancer. They showed that this protein is degraded in cancers, blocking the cellular off-switch of a feedback loop involving the inflammatory protein interleukin-6 (IL-6). When the switch does not get turned off, it enables cancer stem cells to grow.
“We have known for a long time that there are important links between inflammation and cancer, including similar pathways that regulate normal and cancer stem cells,” said study author Max S. Wicha, MD, director of the U-M Comprehensive Cancer Center.
“This work helps explain why these pathways shut off in normal tissues after injury but remain active in cancers, resulting in an increase in cancer stem cells. Furthermore, they suggest that blocking these inflammatory loops may be a means of targeting cancer stem cells, improving patient outcome,” Wicha said. The study appears in Oncogene (2014; doi:10.1038/onc.2014.4).
Currently, there are no molecularly targeted therapies aimed at triple-negative breast cancer, which is a type of cancer negative for estrogen receptor, progesterone receptor, and the human epidermal growth factor receptor 2 (HER2) protein—all key targets for current therapies. Patients with this form of disease tend to have worse outcomes.
The researchers tested a drug, bortezomib, in mouse models of triple-negative breast cancer and found that it stops the protein degradation, resulting in the inflammatory loop shutting off, which reduces the cancer stem cells, thereby blocking metastasis. Bortezomib is currently approved for the treatment of the blood cancer multiple myeloma.
This team previously showed that IL-6 can stimulate breast cancer stem cells in HER2-positive breast cancers and they are designing a clinical trial which uses an IL-6 blocker. The new research suggests that adding bortezomib to the IL-6 inhibitor may be a way to target stem cells in triple-negative breast cancer.
“Now that we unveiled how inflammation is regulated in triple-negative breast cancer, we expect that our studies can be translated into the clinic. The drugs used to block these chemical messengers are already approved for the treatment of rheumatoid arthritis and other inflammation-related diseases, which should facilitate their use in cancer,” said study author Hasan Korkaya, PhD, assistant professor at the Georgia Regents University Cancer Center.
More laboratory testing is needed before a clinical trial can begin. The researchers also suspect that this pathway may apply to other cancers as well and are investigating that further.