Research ArticleCancer

IL-25 Causes Apoptosis of IL-25R–Expressing Breast Cancer Cells Without Toxicity to Nonmalignant Cells

Science Translational Medicine  13 Apr 2011:
Vol. 3, Issue 78, pp. 78ra31
DOI: 10.1126/scitranslmed.3001374

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Breast Tissue, Heal Thyself

Actors and their audiences alike prefer multidimensional characters because they’re more realistic than the limited good-guy, bad-guy personifications and thus reveal subtle nuances about the human condition. Similarly, when the stage consists of a three-dimensional (3D) matrix designed to mimic the in vivo tumor microenvironment, cellular actors play more complex roles and can display previously unappreciated intricacies of human biology. During development, the cradling microenvironment cooperates with cells in the creation of tissues and organs. Because cellular growth control is central to the tissue development process, researchers have suggested that under some conditions, normal cells might secrete substances that could stymie neighboring tumor cells that materialize in the midst of normal ones. Now, Furuta et al. find that normal mammary epithelial cells (MECs) deliver an anticancer cytokine, interleukin-25 (IL-25), and show that signaling through the IL-25 receptor (IL-25R) may constitute a new therapeutic target for certain breast cancers.

Epithelial cells are known to function in tissue development and to produce factors that regulate the growth and differentiation of other adjacent cells. The authors cultured nonmalignant MECs on a 3D laminin-rich matrix that directed the formation of 3D acini—clusters of cells that form the glandular epithelium organized around a lumen into which cellular products are secreted. Using mass spectrometry analysis of the medium and functional assays, Furuta et al. identified six factors secreted by MECs that killed breast cancer cells grown in the 3D culture. The most potent assassin, IL-25, induced caspase-mediated apoptosis in cultured breast cancer cells that expressed IL-25R, but had no detrimental effect on nonmalignant MECs, which expressed only miniscule amounts of IL-25R. To investigate the potential in vivo role of IL-25R in breast cancer, the authors assessed whether the protein existed on the surface of tumor cells from patients and found that IL-25R was expressed in the greatest amounts on tumors from patients who had poor prognoses. Furthermore, IL-25 blocked the growth of IL-25R–expressing mammary tumors in animals but had no toxic effect on normal tissues. These findings suggest that targeting of the IL-25R signaling pathway may be a viable therapeutic approach for advanced breast cancer.

It remains unknown how IL-25R imparts a growth advantage on breast cancer cells. The authors report that about one-third of the breast cancer biopsies tested, but not normal mammary cells, produce large amounts of another IL-25R ligand called IL-17B, which might compete with IL-25 for binding to the receptor. When IL-17B synthesis was blocked, with a small inhibitory RNA molecule, in cultured breast cancer cells, they lost their ability to proliferate and invade; subsequent addition of the cytokine restored these functions. The authors are currently deciphering whether IL-17B enhances, in an autocrine fashion, the tumorigenic potential of breast cancer cells that express IL-25R. In contrast to IL-17B, addition of IL-25 to IL-17B–expressing breast cancer cells induced apoptosis; this was not a surprising result, because IL-25 is known to bind IL-25R with a higher affinity than does IL-17B. Furuta et al. hypothesize that it is the spatial and temporal expression of cytokines that determines whether IL-25R–expressing tumors divide or die in vivo. Thus, in the context of mammary tumor development, which actor steals the show depends upon which one is on stage and where we are in the dramatic arc. IL-25 secreted by the surrounding epithelia might kill individual IL-25R–expressing tumor cells as they form, but if one escapes, then cancer cell secretion of IL-17B might boost tumor growth if there is no IL-25 in the vicinity. Together, the findings of Furuta et al. strengthen the notion that targeting of the IL-25R signaling pathway forms the basis for the discovery of specific breast cancer drugs with broad therapeutic windows.