title: Expression of Iron-Related Proteins Differentiate Non-Cancerous and Cancerous Breast Tumors.
abstract: We have previously reported hepcidin and ferritin increases in the plasma of breast cancer patients, but not in patients with benign breast disease. We hypothesized that these differences in systemic iron homeostasis may reflect alterations in different iron-related proteins also play a key biochemical and regulatory role in breast cancer. Thus, here we explored the expression of a bundle of molecules involved in both iron homeostasis and tumorigenesis in tissue samples. Enzyme-linked immunosorbent assay (ELISA) or reverse-phase protein array (RPPA), were used to measure the expression of 20 proteins linked to iron processes in 24 non-cancerous, and 56 cancerous, breast tumors. We found that cancerous tissues had higher level of hepcidin than benign lesions (p = 0.012). The univariate analysis of RPPA data highlighted the following seven proteins differentially expressed between non-cancerous and cancerous breast tissue: signal transducer and transcriptional activator 5 (STAT5), signal transducer and activator of transcription 3 (STAT3), bone morphogenetic protein 6 (BMP6), cluster of differentiation 74 (CD74), transferrin receptor (TFRC), inhibin alpha (INHA), and STAT5_pY694. These findings were confirmed for STAT5, STAT3, BMP6, CD74 and INHA when adjusting for age. The multivariate statistical analysis indicated an iron-related 10-protein panel effective in separating non-cancerous from cancerous lesions including STAT5, STAT5_pY694, myeloid differentiation factor 88 (MYD88), CD74, iron exporter ferroportin (FPN), high mobility group box 1 (HMGB1), STAT3_pS727, TFRC, ferritin heavy chain (FTH), and ferritin light chain (FTL). Our results showed an association between some iron-related proteins and the type of tumor tissue, which may provide insight in strategies for using iron chelators to treat breast cancer.
authors.affiliation: Unit of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. sara.pizzamiglio@istitutotumori.mi.it.
authors.forename: Sara
authors.initials: S
authors.lastname: Pizzamiglio
authors.affiliation: Proteomics Laboratory, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Maida
authors.initials: M
authors.lastname: De Bortoli
authors.affiliation: Proteomics Laboratory, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. elena.taverna@istitutotumori.mi.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Taverna
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy. michele.signore@iss.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Signore
authors.affiliation: DOSMM, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. silvia.veneroni@istitutotumori.mi.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Veneroni
authors.affiliation: Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China. chocs@ha.org.hk.
authors.forename: William Chi-Shing
authors.initials: WC
authors.lastname: Cho
authors.affiliation: Molecular Targets Unit, Fondazione IRCCS Istituto Nazionale dei Tumouri, 20133 Milan, Italy. rosaria.orlandi@istitutotumori.mi.it.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Orlandi
authors.affiliation: Unit of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. paolo.verderio@istitutotumori.mi.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Verderio
authors.affiliation: Proteomics Laboratory, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. italia.bongarzone@istitutotumori.mi.it.
authors.forename: Italia
authors.initials: I
authors.lastname: Bongarzone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001798:Blood Proteins; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D003937:Diagnosis, Differential; D004797:Enzyme-Linked Immunosorbent Assay; D004921:Erythropoietin / Q000097:blood; D005260:Female; D005293:Ferritins / Q000378:metabolism; D064451:Hepcidins / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D007501:Iron / Q000378:metabolism*; D008875:Middle Aged; D040081:Protein Array Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D001798:Blood Proteins; D064451:Hepcidins; D015850:Interleukin-6; D011506:Proteins; D011990:Receptors, Transferrin; D004921:Erythropoietin; D005293:Ferritins; D007501:Iron
keywords: Iron; STAT5; breast cancer; ferroportin; hepcidin; iron chelators; metabolism; reverse phase protein array; transferrin receptor (TFR)