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Autocrine Production of Interleukin 6 Causes Multidrug Resistance in Breast Cancer Cells¹

Section of Immunobiology, Department of Medicine [D. C., L. W., P. S. R., M. R.] and Pathology Department [D. W.], University of Vermont, Burlington, Vermont 05405; Department of Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Pocatello, Idaho 83209 [A. B.]; and Eukaryotic Transcriptional Regulation Section, Regulation of Cell Growth Laboratory, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702 [P. J.]

It has been shown that serum levels of interleukin (IL)-6 are elevated in patients with various types of cancer. However, the exact source of IL-6 in these patients and its role in tumor progression remain unclear. Here we demonstrate that the autocrine production of IL-6 by tumor cells promotes resistance of the cells to chemotherapy, a novel function of IL-6 in cancer biology. Breast cancer cells that are sensitive to drug treatment do not express IL-6, whereas high levels of IL-6 are produced by multidrug-resistant breast cancer cells. Expression of the IL-6 gene in drug-sensitive breast cancer cells increases their resistance to drug treatment by activating the CCAAT enhancer-binding protein family of transcription factors and inducing mdr1 gene expression. Thus, the autocrine production of IL-6 by tumor cells is an important factor in determining the susceptibility or resistance of these cells to drug treatment. Because tumors from some breast cancer patients contain IL-6-producing cells, it is possible that IL-6 could potentially be used as a prognostic factor for chemotherapy resistance.

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