Aberrant Expression of TfR1/CD71 in Thyroid Carcinomas Identifies a Novel Potential Diagnostic Marker and Therapeutic Target Gaetano Magro, 1 Ivana Cataldo, 2 Paolo Amico, 1 Antonietta Torrisi, 3 Giada Maria Vecchio, 1 Rosalba Parenti, 4 Sofia Asioli, 5 Daniele Recupero, 5 Velia D’Agata, 6 Maria Teresa Mucignat, 7 and Roberto Perris 7,8 Background: Type I receptor for transferrin (TfR1/CD71) is overexpressed in several malignant tumors, but no studies are available on thyroid carcinomas. Our previous comparative analyses of the relative distribution of transferrin in benign versus papillary thyroid carcinoma (PTC) tissues highlighted a marked malignancy- associated abundance of the molecule. The aim of the present study was to evaluate whether TfR1/CD71 is also differentially expressed in benign versus malignant thyroid tissues. Methods: Tissue samples, including benign lesions and follicular-derived carcinomas, from 241 patients and a total of 35 benign and malignant fresh specimens were assayed for TfR1/CD71 expression by reverse tran- scriptase-polymerase chain reaction, Western blot, and immunohistochemistry. Results: We found that transcription of TfR1/CD71 gene is constitutive in thyroid epithelia, but the mRNA is differently translated in benign and malignant tissues. Western blot revealed higher levels of TfR1/CD71 protein in malignant versus benign tissues. Immunohistochemically, most carcinomas exhibited overexpression of the receptor, predominantly in the cytoplasm of neoplastic cells. The highest expression level was detected in primary and metastatic papillary carcinomas and anaplastic carcinomas, with positive results ranging from 86% to 100% of the cases. In contrast, most benign tissues were negative, with only a minority of cases showing focal and weak immunoreactivity. Conclusions: Our findings suggest that altered expression of TfR1/CD71 may be used as a marker helpful in distinguishing PTC from papillary hyperplasia and follicular variant PTC from benign follicular-patterned lesions. Additionally, the present observations support the rationale for the use of radiolabeled transferrin/ transferrin analogs and/or anti-TfR1/CD71 antibodies for diagnostic and/or radiotherapeutic purposes in TfR1/CD71-expressing thyroid tumors. Introduction T ype I receptor for transferrin (TfR1), also known as CD71, is a transmembrane type II glycoprotein ubiqui- tously expressed on the cell surface, which plays a key role in homeostasis of intracellular iron transport (1). A number of studies have suggested that TfR1/CD71 additionally may be implicated in the regulation of cell growth (1–3) and, in fact, this receptor is known to be expressed at low levels in normal quiescent cells, while being upregulated in cells with high proliferative index, such as the cells of the epidermal basal layer, intestinal epithelial cells, and cancer cells (1,4–8). This can be explained by the increased need for iron of divid- ing cells, as this metal acts as a cofactor in many enzymatic 1 Department G.F. Ingrassia, Azienda Ospedaliero-Universitaria ‘‘Policlinico-Vittorio Emanuele,’’ Anatomic Pathology, University of Catania, Catania, Italy. 2 Department of Pathology, University of Verona, Verona, Italy. 3 Department G.F Ingrassia, Integrated Tumor Registry of Messina-Catania-Siracusa, Hygiene and Public Health Institute, Catania, Italy. 4 Department of Physiological Sciences, University of Catania, Catania, Italy. 5 Department of Biomedical Sciences and Human Oncology, University of Turin, Turin, Italy. 6 Section of Anatomy, Department G.F. Ingrassia, University of Catania, Catania, Italy. 7 Division for Experimental 2, The National Tumour Institute Aviano, CRO-IRCCS, Aviano (PN), Italy. 8 COMT–Centre for Molecular and Translational Oncology, University of Parma, Parma, Italy. THYROID Volume 21, Number 3, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089/thy.2010.0173 267