title: Interleukin-6 and pro inflammatory status in the breast tumor microenvironment.
abstract: BACKGROUND
  Greater than 50,000 new cases of breast cancer cases were diagnosed in Italy during 2013, with nearly 15,000 women succumbing to the disease. These epidemiological statistics highlight the overwhelming clinical dilemma of breast cancer and emphasize the need for novel therapeutic targets and prevention strategies. Countless studies in the fields of mammary gland development and breast cancer have led to an appreciation of a breast tumor microenvironment that actively contributes to the heterogeneous nature of breast cancer.
  
  
  METHODS
  The current review will focus on the impact of IL-6 and in the breast tumor microenvironment. Excessive IL-6 has been demonstrated in primary breast tumors and breast cancer patient sera and is associated with poor clinical outcomes in breast cancer. These clinical associations are corroborated by emerging preclinical data revealing that IL-6 is a potent growth factor and promotes an epithelial-mesenchyme (EMT) phenotype in breast cancer cells to indicate that IL-6 in the breast tumor microenvironment is clinically relevant.
  
  
  RESULTS
  High serum levels of interleukin-6 correlate with poor outcome in breast cancer patients. However, few data are yet available on the relationship between IL-6 and stem/progenitor cells, which may fuel the genesis of breast cancer in vivo. Mammospheres (MS) from node invasive breast carcinoma tissues express IL-6 mRNA at higher levels than MS from matched non-neoplastic mammary glands. IL-6 mRNA is detectable only in basal-like breast carcinoma tissues; our results reveal that IL-6 triggers a Notch-3-dependent upregulation of the Notch ligand Jagged-1, whose interaction with Notch-3 promotes the growth of MS and Michigan Cancer Foundation-7 (MCF-7)-derived spheroids. IL-6 induces a Notch-3-dependent upregulation of the carbonic anhydrase IX gene and promotes a hypoxia-resistant/invasive phenotype in MCF-7 cells and MS.
  
  
  CONCLUSIONS
  In conclusion, our 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.
authors.affiliation: Struttura Complessa di Chirurgia Generale e Specialità Chirurgiche Azienda Ospedaliera 'Santa Maria', University of Perugia Azienda Ospedaliera Terni, Viale Tristano di Joannuccio, 105100, Terni, Italy. sanguinettiale@gmail.com.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sanguinetti
authors.affiliation: U.O. di Anatomia Patologica, Azienda Ospedaliera Policlinico S. Orsola-Malpighi, Bologna, Italy. donatella.santini@aosp.bo.it.
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Università di Bologna, Via Zamboni, 40126, Bologna, Italy. massimiliano.bonafe@unibo.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonafè
authors.affiliation: Dipartimento di Chirurgia generale e dei trapianti d'organo, Azienda Ospedaliera Policlinico S. Orsola-Malpighi, Via Pietro Albertoni, 40138, Bologna, Italy. mario.taffurelli@aosp.bo.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Taffurelli
authors.affiliation: Struttura Complessa di Chirurgia Generale e Specialità Chirurgiche Azienda Ospedaliera 'Santa Maria', University of Perugia Azienda Ospedaliera Terni, Viale Tristano di Joannuccio, 105100, Terni, Italy. nicolaavenia@libero.it.
authors.forename: Nicola
authors.initials: N
authors.lastname: Avenia
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001940:Breast / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; C499374:NOTCH3 protein, human; D012333:RNA, Messenger; D000071656:Receptor, Notch3; D051880:Receptors, Notch