High serum levels of IL-6 correlate with poor outcome in breast cancer patients. However, no data are available on the relationship between IL-6 and mammary stem/progenitor cells, which may fuel the genesis of breast cancer in vivo. Herein, we address this issue in the MCF-7 breast cancer cell line and in primary human mammospheres (MS), multicellular structures enriched in stem/progenitor cells of the mammary gland. MS from node invasive breast carcinoma tissues expressed IL-6 mRNA at higher levels than did MS from matched non-neoplastic mammary glands. In addition, IL-6 mRNA was detected only in basal-like breast carcinoma tissues, an aggressive breast carcinoma variant showing stem cell features. IL-6 treatment triggered Notch-3–dependent upregulation of the Notch ligand Jagged-1 and promotion of MS and MCF-7–derived spheroid growth. Moreover, IL-6 induced Notch-3–dependent upregulation of the carbonic anhydrase IX gene and promoted a hypoxia-resistant/invasive phenotype in MCF-7 cells and MS. Finally, autocrine IL-6 signaling relied upon Notch-3 activity to sustain the aggressive features of MCF-7–derived hypoxia-selected cells. In conclusion, these data support the hypothesis that IL-6 induces malignant features in Notch-3–expressing stem/progenitor cells from human ductal breast carcinoma and normal mammary gland.
Pasquale Sansone, Gianluca Storci, Simona Tavolari, Tiziana Guarnieri, Catia Giovannini, Mario Taffurelli, Claudio Ceccarelli, Donatella Santini, Paola Paterini, Kenneth B. Marcu, Pasquale Chieco, Massimiliano Bonafè