Scientists from the University of Michigan Comprehensive Cancer Center and Georgia Regents University report that a protein that fuels an inflammatory pathway does not turn off in breast cancer, resulting in an increase in cancer stem cells. The finding provides a potential target for treating triple-negative breast cancer, the most aggressive form of the disease, according to the researchers who published their study (“SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer mode”) in Oncogene.
The researchers identified a protein, SOCS3, that 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 (IL6). When the switch does not get turned off, it enables cancer stem cells to grow.
“In nontransformed cells, transient activation of the IL6 inflammatory loop induced SOCS3 expression leading to pathway inactivation. In transformed cells, enforced expression of SOCS3 or interfering with IL6 pathway via IL6R blockade inhibited tumor growth and metastasis in mouse xenograft models,” write the investigators in the current study. “Furthermore, circulating tumor cells were significantly reduced in tumor-bearing animals when treated with anti-IL6R antibodies. These studies uncover important connections between inflammation and carcinogenesis and suggest that blocking pro-inflammatory cytokines may be utilized as an attractive strategy to target triple-negative breast tumors, which currently lacks molecularly targeted therapies.”
Scientists have long known that there are important links between inflammation and cancer including similar pathways that regulate normal and cancer stem cells, explains study author Max S. Wicha, M.D., distinguished professor of oncology and 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,” he says.
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 HER2 protein –all major 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 treatment of the blood cancer multiple myeloma.
“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,” says study author Hasan Korkaya, Ph.D., 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.