IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland.
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.
Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, Department of Pharmacology and Toxicology, University of Bologna, Bologna, Italy.
Pasquale
P
Sansone
Gianluca
G
Storci
Simona
S
Tavolari
Tiziana
T
Guarnieri
Catia
C
Giovannini
Mario
M
Taffurelli
Claudio
C
Ceccarelli
Donatella
D
Santini
Paola
P
Paterini
Kenneth B
KB
Marcu
Pasquale
P
Chieco
Massimiliano
M
Bonafè
D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D019898:Autocrine Communication / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis / Q000235:genetics; D044584:Carcinoma, Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000072100:Jagged-1 Protein; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D018874:Spheroids, Cellular / Q000378:metabolism* / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D000951:Antigens, Neoplasm; D002135:Calcium-Binding Proteins; C508600:IL6 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C499374:NOTCH3 protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases