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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.

SUBMITTER: Pizzamiglio S

PROVIDER: S-EPMC5343944 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Expression of Iron-Related Proteins Differentiate Non-Cancerous and Cancerous Breast Tumors.

Pizzamiglio Sara S De Bortoli Maida M Taverna Elena E Signore Michele M Veneroni Silvia S Cho William Chi-Shing WC Orlandi Rosaria R Verderio Paolo P Bongarzone Italia I

International journal of molecular sciences 20170214 2

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 immunosorb ...[more]

PMID: 28216608

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Project description:BackgroundThe insulin receptor (INSR) and the insulin growth factor 1 receptor (IGF1R) play important roles in the etiology of both diabetes mellitus and breast cancer. We aimed to evaluate the expression of hormone and insulin-related proteins within or related to the PI3K and MAPK pathway in breast tumors of women with or without diabetes mellitus, treated with or without insulin (analogues).MethodsImmunohistochemistry was performed on tumor tissue of 312 women with invasive breast cancer, with or without pre-existing diabetes mellitus, diagnosed in 2000-2010, who were randomly selected from a Danish breast cancer cohort. Women with diabetes were 2:1 frequency matched by year of birth and age at breast cancer diagnosis to those without diabetes. Tumor Microarrays were successfully stained for p-ER, EGFR, p-ERK1/2, p-mTOR, and IGF1R, and scored by a breast pathologist. Associations of expression of these proteins with diabetes, insulin treatment (human insulin and insulin analogues) and other diabetes medication were evaluated by multivariable logistic regression adjusting for menopause and BMI; effect modification by menopausal status, BMI, and ER status was assessed using interactions terms.ResultsWe found no significant differences in expression of any of the proteins in breast tumors of women with (n?=?211) and without diabetes (n?=?101). Among women with diabetes, insulin use (n?=?53) was significantly associated with higher tumor protein expression of IGF1R (OR?=?2.36; 95%CI:1.02-5.52; p?=?0.04) and p-mTOR (OR?=?2.35; 95%CI:1.13-4.88; p?=?0.02), especially among women treated with insulin analogues. Menopause seemed to modified the association between insulin and IGF1R expression (p?=?0.07); the difference in IGF1R expression was only observed in tumors of premenopausal women (OR?=?5.10; 95%CI:1.36-19.14; p?=?0.02). We found no associations between other types of diabetes medication, such as metformin, and protein expression of the five proteins evaluated.ConclusionsIn our study, breast tumors of women with pre-existing diabetes did not show an altered expression of selected PI3K/MAPK pathway-related proteins. We observed an association between insulin treatment and increased p-mTOR and IGF1R expression of breast tumors, especially in premenopausal women. This observation, if confirmed, might be clinically relevant since the use of IGF1R and mTOR inhibitors are currently investigated in clinical trials.

Dataset Information

Expression of Iron-Related Proteins Differentiate Non-Cancerous and Cancerous Breast Tumors.

Publications

Expression of Iron-Related Proteins Differentiate Non-Cancerous and Cancerous Breast Tumors.

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