Researchers have identified the IL-25 signalling pathway as a potential new target for the treatment of breast cancer. Work by a team at the Lawrence Berkeley National Laboratory has shown that the natural secretion of IL-25 by developing nonmalignant mammary epithelial cells (MECs) directly causes the death of breast cancer cells expressing the IL-25 receptor. Their work found that IL-25 not only triggered apoptosis in IL-25 receptor-expressing tumor cells in vitro, but also shrank tumors in mice grafted with human tumors. Conversely, the cytokine had no effect on noncancerous cells, which don’t express the IL-25 receptor, or on cancerous cells that only express very low levels of the receptor.
When the researchers then looked at tumor samples from breast cancer patients, they found that a high level of IL-25 receptor expression correlated with poor prognosis, suggesting that receptor expression could also represent a useful marker for breast cancer diagnosis and future targeted therapeutics. The research is published in Science Translational Medicine, in a paper titled, “IL-25 Causes Apoptosis of IL-25R–Expressing Breast Cancer Cells Without Toxicity to Nonmalignant Cells.” The work was carried out in collaboration with researchers at the National Taiwan University Hospital in Taipei, and the University of California’s College of Medicine.
The Berkeley-led team, headed by Mina Bussel, Ph.D., isolated six compounds expressed by normal MECs but not cancerous breast cells. These included the antiangiogenic proteins antithrombin III and vitamin D–binding protein, along with the proinflammatory cytokines IL-1F7 and IL-25 (which is also known as IL-17E), and the growth and differentiation proteins bone morphogenic protein 10 and fibroblast growth factor 11. However, while most of these factors were found to have a cytostatic effect on cancer cells, IL-25 had a marked cytotoxic effect.
Results from tests on xenografted mice were particularly encouraging. When the researchers tested the effects of the cytokine on human tumors grafted in mice, they found that IL-25 treatment significantly held back cancerous growth. After a month, the average size of the treated tumors was threefold smaller than that of the control tumors.
Subsequent examination and comparison of xenograft tumors excised from IL-25–treated and untreated controls showed the treated samples contained about 50% fewer actively dividing tumor cells that exhibited an average mitotic index that was half that of untreated tumors. Moreover, in some of the IL-25–treated mice, the tumors had regressed completely, and the lesion contained only lymphocytic infiltrates.
Having confirmed that IL-25 treatment significantly reduced tumor growth in these animals, the team went on to assess the systemic stress and toxicity caused by the treatment. They found IL-25 administration, and subsequent pathological analysis of various organs from the untreated and IL-25–treated mice, found no evidence of pathologies. Even mice injected with much higher doses of IL-25 showed no signs of illness.
A hint as to why breast cancer cells express high levels of IL-25 receptors was gleaned when the team depleted IL-25R from a panel of breast cancer cell lines using an IL-25R–specific small-interfering RNA (siRNA) and measured the ability of the resulting cells to grow anchorage independently in soft agar. Reduction of IL-25R markedly inhibited the growth of all the cancer cell lines tested by 75-85%, indicating that IL-25R is important for their anchorage-independent growth, they note.
“Since IL-25 is produced by healthy breast tissue as a natural defense mechanism against cancer during the cell differentiation process, we should be able to utilize IL-25/IL-25 receptor signalling as an organic approach to breast cancer therapy,” concludes Berkeley co-author Saori Furuta, Ph.D.
The researchers are now looking at the other five other cytostatic proteins they found were secreted by normal breast cancer cells, to see whether combining one or more of these molecules with IL-25 could provide an effective therapy against aggressive breast and other cancers.