Anlotinib plus icotinib as a potential treatment option for EGFR-mutated advanced non-squamous non-small cell lung cancer with concurrent mutations: final analysis of the prospective phase 2, multicenter ALTER-L004 study.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and concurrent mutations have a poor prognosis. This study aimed to examine anlotinib plus icotinib as a first-line treatment option for advanced NSCLC carrying EGFR mutation with or without concurrent mutations. METHODS: This phase 2, single-arm, multicenter trial (ClinicalTrials.gov NCT03736837) was performed at five hospitals in China from December 2018 to November 2020. Non-squamous NSCLC cases with EGFR-sensitizing mutations were treated with anlotinib and icotinib. The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. RESULTS: Sixty participants were enrolled, including 31 (52%) and 29 (48%) with concurrent mutations and pathogenic concurrent mutations, respectively. The median follow-up was 26.9 (range, 15.0-38.9) months. ORR and DCR were 68.5% and 98.2%, respectively. Median PFS was 15.1 (95%CI: 12.6-17.6) months which met the primary endpoint, median DoR was 13.5 (95%CI: 10.0-17.1) months, and median OS was 30.0 (95%CI: 25.5-34.5) months. Median PFS and OS in patients with pathogenic concurrent mutations were 15.6 (95%CI: 12.5-18.7) months and not reached (95%CI: 17.46 months to not reached), respectively. All patients experienced TRAEs, including 26 (43%) and 1 (1.7%) who had grade ≥ 3 and serious treatment-related adverse events (TRAEs). CONCLUSIONS: Anlotinib combined with icotinib was effective and well-tolerated as a first-line treatment option for EGFR mutation-positive advanced NSCLC with or without concurrent mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03736837.

Curcumin potentiates the ErbB receptors inhibitor Afatinib for enhanced antitumor activity in malignant mesothelioma.

Several attempts have been made to develop targeted therapies for malignant mesothelioma (MM), an aggressive tumour with a poor prognosis. In this study we evaluated whether Curcumin (CUR) potentiated the antitumor activity of the ErbB receptors inhibitor Afatinib (AFA) on MM, employing cell lines cultured in vitro and mice bearing intraperitoneally transplanted, syngeneic MM cells. The rationale behind this hypothesis was that CUR could counteract mechanisms of acquired resistance to AFA. We analysed CUR and AFA effects on MM cell growth, cell cycle, autophagy, and on the modulation of tumour-supporting signalling pathways.This study demonstrated that, as compared to the individual compounds, the combination of AFA + CUR had a stronger effect on MM progression which can be ascribed either to increased tumour cell growth inhibition or to an enhanced pro-apoptotic effect. These results warrant future studies aimed at further exploring the therapeutic potential of AFA + CUR-based combination regimens for MM treatment.

Altered gene expression due to aberrant DNA methylation correlates with responsiveness to anti-EGFR antibody treatment.

The cetuximab gene expression signature and DNA methylation status of colorectal cancer (CRC) are predictive of the therapeutic effects of anti-epidermal growth factor receptor (EGFR) antibody therapy. As DNA methylation is a means of regulating gene expression, it may play an important role in the expression of cetuximab signature genes. This study aims to determine the effects of aberrant DNA methylation on the regulation of cetuximab signature gene expression. Comprehensive DNA methylation and gene expression data were retrieved from CRC patients in three tumor tissue (TT) cohorts and three normal colorectal mucosa/tumor tissue paired (NCM-TT) cohorts. Of the 231 cetuximab signature genes, 57 exhibited an inverse correlation between the methylation of promoter CpG sites and gene expression level in multiple cohorts. About two-thirds of the promoter CpG sites associated with the 57 genes exhibited this correlation. In all 57 gene promoter regions, the methylation levels in NCMs did not differ according to comparisons based on cetuximab signature or DNA methylation status classification of matched TTs. Thus, the altered expression of 57 genes was caused by aberrant DNA methylation during carcinogenesis. Analysis of the association between cetuximab signature or DNA methylation status and progression-free survival (PFS) of anti-EGFR antibody agents in the same cohort showed that DNA methylation status was most associated with PFS. In conclusion, we found that aberrant DNA methylation regulates specific gene expression in cetuximab signature during carcinogenesis, suggesting that it is one of the important determinants of sensitivity to anti-EGFR antibody agents.

Combined treatment with inhibitors of ErbB Receptors and Hh signaling pathways is more effective than single treatment in reducing the growth of malignant mesothelioma both in vitro and in vivo.

Malignant mesothelioma (MM) is a rare orphan aggressive neoplasia with low survival rates. Among the other signaling pathways, ErbB receptors and Hh signaling are deregulated in MM. Thus, molecules involved in these signaling pathways could be used for targeted therapy approaches. The aim of this study was to evaluate the effects of inhibitors of Hh- (GANT-61) and ErbB receptors (Afatinib)-mediated signaling pathways, when used alone or in combination, on growth, cell cycle, cell death and autophagy, modulation of molecules involved in transduction pathways, in three human MM cell lines of different histotypes. The efficacy of the combined treatment was also evaluated in a murine epithelioid MM cell line both in vitro and in vivo. This study demonstrated that combined treatment with two inhibitors counteracting the activation of two different signaling pathways involved in neoplastic transformation and progression, such as those activated by ErbB and Hh signaling, is more effective than the single treatments in reducing MM growth in vitro and in vivo. This study may have clinical implications for the development of targeted therapy approaches for MM.

Role of glycosyltransferases in carcinogenesis; growth factor signaling and EMT/MET programs.

The glycosylation of cell surface receptors has been shown to regulate each step of signal transduction, including receptor trafficking to the cell surface, ligand binding, dimerization, phosphorylation, and endocytosis. In this review we focus on the role of glycosyltransferases that are involved in the modification of N-glycans, such as the effect of branching and elongation in signaling by various cell surface receptors. In addition, the role of those enzymes in the EMT/MET programs, as related to differentiation and cancer development, progress and therapy resistance is discussed.

Prospective case series of neuropathic cancer pain in patients treated with an EGFR-inhibitor.

BACKGROUND: Novel treatments of neuropathic pain are urgently needed. Rapid relief of neuropathic cancer pain in patients treated with epidermal growth factor receptor (EGFR) inhibitors have been reported. Experiments in rodent models confirm the pain relief and reveal novel mechanisms critically involving the EGFR. Clinical pain research is complicated and patients with advanced cancer are heterogeneous, often with complex, deteriorating clinical pictures, hampering feasibility of drug-trial procedures. ACTUAL CASE: Prospective case series exploring the EGFR inhibition/neuropathic cancer pain association in order to inform planning clinical trials. POSSIBLE COURSES OF ACTION: Symptom assessment method was tailored to what was ethical, feasible, and clinically relevant for each patient. FORMULATION OF A PLAN: Patients with neuropathic cancer pain treated off-label with the monoclonal antibody panitumumab were studied to assess feasibility of different measurement tools. OUTCOME: Fourteen of 20 patients (70%) experienced clinically significant pain relief. There was good concordance in patient and physician-reported outcomes. LESSONS: Results support panitumumab's potential to be of significant benefit to patients with refractory neuropathic cancer pain. Findings also reinforce the difficulty of using conventional drug trial endpoints and designs in this population. VIEW: Innovative research methods must be considered for much needed pivotal trials.

PDCD4 limits prooncogenic neuregulin-ErbB signaling.

The neuregulins and their ErbB/HER receptors play essential roles in mammalian development and tissue homeostasis. In addition, deregulation of their function has been linked to the pathogenesis of diseases such as cancer or schizophrenia. These circumstances have stimulated research into the biology of this ligand-receptor system. Here we show the identification of programmed cell death protein-4 (PDCD4) as a novel neuregulin-ErbB signaling mediator. Phosphoproteomic analyses identified PDCD4 as protein whose phosphorylation increased in cells treated with neuregulin. Mutagenesis experiments defined serine 67 of PDCD4 as a site whose phosphorylation increased upon activation of neuregulin receptors. Phosphorylation of that site promoted degradation of PDCD4 by the proteasome, which depended on exit of PDCD4 from the nucleus to the cytosol. Mechanistic studies defined mTORC1 and ERK1/2 as routes implicated in neuregulin-induced serine 67 phosphorylation and PDCD4 degradation. Functionally, PDCD4 regulated several important biological functions of neuregulin, such as proliferation, migration, or invasion.

Gene therapy for overexpressing Neuregulin 1 type I in skeletal muscles promotes functional improvement in the SOD1G93A ALS mice.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motoneurons (MNs), with no effective treatment currently available. The molecular mechanisms that are involved in MN death are complex and not fully understood, with partial contributions of surrounding glial cells and skeletal muscle to the disease. Neuregulin 1 (NRG1) is a trophic factor highly expressed in MNs and neuromuscular junctions. Recent studies have suggested a crucial role of the isoform I (NRG1-I) in the collateral reinnervation process in skeletal muscle, and NRG1-III in the preservation of MNs in the spinal cord, opening a window for developing novel therapies for neuromuscular diseases like ALS. In this study, we overexpressed NRG1-I widely in the skeletal muscles of the SOD1G93A transgenic mouse. The results show that NRG1 gene therapy activated the survival pathways in muscle and spinal cord, increasing the number of surviving MNs and neuromuscular junctions and reducing the astroglial reactivity in the spinal cord of the treated SOD1G93A mice. Furthermore, NRG1-I overexpression preserved motor function and delayed the onset of clinical disease. In summary, our data indicates that NRG1 plays an important role on MN survival and muscle innervation in ALS, and that viral-mediated overexpression of NRG1 isoforms may be considered as a promising approach for ALS treatment.

EGF and NRG induce phosphorylation of HER3/ERBB3 by EGFR using distinct oligomeric mechanisms.

Heteromeric interactions between the catalytically impaired human epidermal growth factor receptor (HER3/ERBB3) and its catalytically active homologs EGFR and HER2 are essential for their signaling. Different ligands can activate these receptor pairs but lead to divergent signaling outcomes through mechanisms that remain largely unknown. We used stochastic optical reconstruction microscopy (STORM) with pair-correlation analysis to show that EGF and neuregulin (NRG) can induce different extents of HER3 clustering that are dependent on the nature of the coexpressed HER receptor. We found that the presence of these clusters correlated with distinct patterns and mechanisms of receptor phosphorylation. NRG induction of HER3 phosphorylation depended on the formation of the asymmetric kinase dimer with EGFR in the absence of detectable higher-order oligomers. Upon EGF stimulation, HER3 paralleled previously observed EGFR behavior and formed large clusters within which HER3 was phosphorylated via a noncanonical mechanism. HER3 phosphorylation by HER2 in the presence of NRG proceeded through still another mechanism and involved the formation of clusters within which receptor phosphorylation depended on asymmetric kinase dimerization. Our results demonstrate that the higher-order organization of HER receptors is an essential feature of their ligand-induced behavior and plays an essential role in lateral cross-activation of the receptors. We also show that HER receptor ligands exert unique effects on signaling by modulating this behavior.

Insights on the Functional Interaction between Group 1 Metabotropic Glutamate Receptors (mGluRI) and ErbB Receptors.

It is well-appreciated that phosphorylation is an essential post-translational mechanism of regulation for several proteins, including group 1 metabotropic glutamate receptors (mGluRI), mGluR1, and mGluR5 subtypes. While contributions of various serine/threonine protein kinases on mGluRI modulation have been recognized, the functional role of tyrosine kinases (TKs) is less acknowledged. Here, while describing current evidence supporting that mGluRI are targets of TKs, we mainly focus on the modulatory roles of the ErbB tyrosine kinases receptors-activated by the neurotrophic factors neuregulins (NRGs)-on mGluRI function. Available evidence suggests that mGluRI activity is tightly dependent on ErbB signaling, and that ErbB's modulation profoundly influences mGluRI-dependent effects on neurotransmission, neuronal excitability, synaptic plasticity, and learning and memory processes.

Moonlight human ribosomal protein L13a downregulation is associated with p53 and HER2/neu expression in breast cancer.

Breast cancer is the most common malignancy among females worldwide. Recent studies have shown extra-ribosomal roles of the moonlight ribosomal proteins in the development of human cancers. Accurate quantification of the gene expression level is based on the selection of the reference genes whose expression is independent of cancer properties and patient's characteristics. The aim of this study was the evaluation of the expression level of a previously proposed ribosomal protein as moonlight, L13a (RPL13A), in breast cancer samples and their adjacent tissues. Its association with genes of known roles in developing cancers was also investigated. Traditionally used housekeeping genes were selected and their expression was analyzed in 80 surgically excised breast tissue specimens (40 tumors and 40 tumor-adjacent tissues) by applying three software tools including GeNorm, NormFinder, and BestKeeper to select the most stable reference genes. Then, mRNA expression levels of RPL13A and p53 were evaluated. Additionally, protein expression levels of RPL13A were measured. It was demonstrated that PUM1 and ACTB are the most reliable reference genes and RPL13A is the least stable gene. There was a positive correlation between RPL13A and p53 mRNA expression levels in all the tumor samples. Moreover, significant downregulation of RPL13A expression levels was revealed in HER2+ tumor samples compared to HER2- ones. There was also a marked decrease in p53 mRNA expression levels in HER2+ tumor subtypes. Our results suggest that there is a probable relationship between RPL13A decreased expression with p53 and HER2/neu expression in the breast cancer.

On the Modulatory Roles of Neuregulins/ErbB Signaling on Synaptic Plasticity.

Neuregulins (NRGs) are a family of epidermal growth factor-related proteins, acting on tyrosine kinase receptors of the ErbB family. NRGs play an essential role in the development of the nervous system, since they orchestrate vital functions such as cell differentiation, axonal growth, myelination, and synapse formation. They are also crucially involved in the functioning of adult brain, by directly modulating neuronal excitability, neurotransmission, and synaptic plasticity. Here, we provide a review of the literature documenting the roles of NRGs/ErbB signaling in the modulation of synaptic plasticity, focusing on evidence reported in the hippocampus and midbrain dopamine (DA) nuclei. The emerging picture shows multifaceted roles of NRGs/ErbB receptors, which critically modulate different forms of synaptic plasticity (LTP, LTD, and depotentiation) affecting glutamatergic, GABAergic, and DAergic synapses, by various mechanisms. Further, we discuss the relevance of NRGs/ErbB-dependent synaptic plasticity in the control of brain processes, like learning and memory and the known involvement of NRGs/ErbB signaling in the modulation of synaptic plasticity in brain's pathological conditions. Current evidence points to a central role of NRGs/ErbB receptors in controlling glutamatergic LTP/LTD and GABAergic LTD at hippocampal CA3-CA1 synapses, as well as glutamatergic LTD in midbrain DA neurons, thus supporting that NRGs/ErbB signaling is essential for proper brain functions, cognitive processes, and complex behaviors. This suggests that dysregulated NRGs/ErbB-dependent synaptic plasticity might contribute to mechanisms underlying different neurological and psychiatric disorders.

Regulation of the ErbB network by the MIG6 feedback loop in physiology, tumor suppression and responses to oncogene-targeted therapeutics.

The ErbB signaling network instructs the execution of key cellular programs, such as cell survival, proliferation and motility, through the generation of robust signals of defined strength and duration. In contrast, unabated ErbB signaling disrupts tissue homeostasis and leads to cell transformation. Cells oppose the threat inherent in excessive ErbB activity through several mechanisms of negative feedback regulation. Inducible feedback inhibitors (IFIs) are expressed in the context of transcriptional responses triggered by ErbB signaling, thus being uniquely suited to regulate ErbB activity during the execution of complex cellular programs. This review focuses on MIG6, an IFI that restrains ErbB signaling by mediating ErbB kinase suppression and receptor down-regulation. We will review key issues in MIG6 function, regulation and tumor suppressor activity. Subsequently, the role for MIG6 loss in the pathogenesis of tumors driven by ErbB oncogenes as well as in the generation of cellular addiction to ErbB signaling will be discussed. We will conclude by analyzing feedback inhibition by MIG6 in the context of therapies directed against ErbB and non-ErbB oncogenes.

HSP90 inhibitor AUY922 can reverse Fulvestrant induced feedback reaction in human breast cancer cells.

Hormone therapy has become one of the main strategies for breast cancer, however, many estrogen receptor (ER) positive patients end in tumor collapse due to initial or acquired resistance to hormone treatment, which includes Fulvestrant. Here we report that ErbB receptors and downstream PI3K/AKT and ERK pathway have been reactivated after treatment of Fulvestrant in ER positive MCF-7 and T47D cells, which are related to Fulvestrant resistance. HSP90 is a universally expressed chaperone protein and plays a vital role in both normal and cancer cells, HSP90 inhibitor AUY922 can reverse this feedback reactivation effect of Fulvestrant by targeting multiple proteins related in ErbB receptors, PI3K/AKT and ERK pathway, which is much better than single targeting inhibitors. We also consolidate these effects in human fresh breast tumors. Combination of AUY922 and Fulvestrant may become a promising therapy strategy in breast cancer treatment.

Piecing it together: Unraveling the elusive structure-function relationship in single-pass membrane receptors.

The challenge of crystallizing single-pass plasma membrane receptors has remained an obstacle to understanding the structural mechanisms that connect extracellular ligand binding to cytosolic activation. For example, the complex interplay between receptor oligomerization and conformational dynamics has been, historically, only inferred from static structures of isolated receptor domains. A fundamental challenge in the field of membrane receptor biology, then, has been to integrate experimentally observable dynamics of full-length receptors (e.g. diffusion and conformational flexibility) into static structural models of the disparate domains. In certain receptor families, e.g. the ErbB receptors, structures have led somewhat linearly to a putative model of activation. In other families, e.g. the tumor necrosis factor (TNF) receptors, structures have produced divergent hypothetical mechanisms of activation and transduction. Here, we discuss in detail these and other related receptors, with the goal of illuminating the current challenges and opportunities in building comprehensive models of single-pass receptor activation. The deepening understanding of these receptors has recently been accelerated by new experimental and computational tools that offer orthogonal perspectives on both structure and dynamics. As such, this review aims to contextualize those technological developments as we highlight the elegant and complex conformational communication between receptor domains. This article is part of a Special Issue entitled: Interactions between membrane receptors in cellular membranes edited by Kalina Hristova.

Expression of the ERBB Family of Ligands and Receptors in Gastric Cancer.

OBJECTIVE: Gastric cancer (GC) is the second most common cancer and the third leading cause of cancer-related death in Korea. Alterations in the ERBB (homology to the erythroblastoma viral gene product, v-erbB) receptor family and ERBB-related signaling pathways are frequently observed in GC. However, the roles of the ERBB receptors and their ligands in GC are not well established. METHODS: We evaluated the expression levels of various ERBB receptor ligands (i.e., heparin-binding epidermal growth factor-like growth factor [HBEGF], transforming growth factor-α [TGFA], amphiregulin [AREG], epiregulin [EREG], epidermal growth factor [EGF], and betacellulin [BTC]) and 3 ERBB family receptors (i.e., epidermal growth factor receptor [EGFR], human EGFR2 [HER2], and ERBB3) in 313 cases of GC using immunohistochemistry, fluorescence in situ hybridization, and mRNA in situ hybridization. RESULTS: A high expression of EGFR, HER2, and ERBB3 was observed in 30, 32, and 27 cases, respectively. A high expression of HBEGF, TGFA, AREG, EREG, EGF, and BTC was observed in 91, 97, 151, 74, 26, and 37 cases, respectively. A high expression of TGFA was associated with better survival, while a high expression of BTC was associated with worse survival. These results were confirmed using Cox proportional hazards analysis. HBEGF, TGFA, AREG, tumor-node-metastasis classification, Lauren's classification, and ERBB3 were significant survival parameters in multivariate analysis. CONCLUSION: Among the ERBB family receptors and ligands examined, 3 ligands (i.e., TGFA, HBEGF, and AREG) and ERBB3 had a prognostic impact.

Epiregulin: roles in normal physiology and cancer.

Epiregulin is a 46-amino acid protein that belongs to the epidermal growth factor (EGF) family of peptide hormones. Epiregulin binds to the EGF receptor (EGFR/ErbB1) and ErbB4 (HER4) and can stimulate signaling of ErbB2 (HER2/Neu) and ErbB3 (HER3) through ligand-induced heterodimerization with a cognate receptor. Epiregulin possesses a range of functions in both normal physiologic states as well as in pathologic conditions. Epiregulin contributes to inflammation, wound healing, tissue repair, and oocyte maturation by regulating angiogenesis and vascular remodeling and by stimulating cell proliferation. Deregulated epiregulin activity appears to contribute to the progression of a number of different malignancies, including cancers of the bladder, stomach, colon, breast, lung, head and neck, and liver. Therefore, epiregulin and the elements of the EGF/ErbB signaling network that lie downstream of epiregulin appear to be good targets for therapeutic intervention.

Afatinib in Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations Pretreated With Reversible EGFR Inhibitors.

BACKGROUND: Afatinib, an irreversible ErbB family blocker, is approved for treatment of patients with previously untreated non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations. Efficacy of afatinib in EGFR tyrosine kinase inhibitor-naïve (TKI-naïve) patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 point mutations) has been reported; however, efficacy in TKI-pretreated patients with uncommon EGFR mutations is unknown. MATERIALS AND METHODS: In the afatinib compassionate use program (CUP), patients with advanced or metastatic, histologically confirmed NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment were enrolled. Demographic data, mutation type, response rates, time to treatment failure (TTF), and safety in patients harboring uncommon EGFR mutations were reported. RESULTS: In 60 patients (63% female, median age 63 years [range: 30-84 years]), a total of 66 uncommon EGFR mutations including 30 T790M mutations were reported (18.4% and 11%, respectively, of known EGFR mutations within the CUP). Most patients (67%) received afatinib as third- or fourth-line treatment. Median TTF was 3.8 months (range: 0.2 to >24.6 months; p = .244) in patients with uncommon mutations compared with 5.1 months (range: 0.1 to >21.1 months) in patients with common mutations (n = 165). Pronounced activity was observed with E709X mutations (TTF >12 months). No new safety signals were detected. CONCLUSION: Afatinib is clinically active and well tolerated in many TKI-pretreated NSCLC patients harboring uncommon EGFR mutations. Compared with results reported in TKI-naïve patients, activity was also indicated in patients with T790M and exon 20 insertion mutations.

Neuregulin-1 is concentrated in the postsynaptic subsurface cistern of C-bouton inputs to α-motoneurons and altered during motoneuron diseases.

C boutons are large, cholinergic, synaptic terminals that arise from local interneurons and specifically contact spinal α-motoneurons (MNs). C boutons characteristically display a postsynaptic specialization consisting of an endoplasmic reticulum-related subsurface cistern (SSC) of unknown function. In the present work, by using confocal microscopy and ultrastructural immunolabeling, we demonstrate that neuregulin-1 (NRG1) accumulates in the SSC of mouse spinal MNs. We also show that the NRG1 receptors erbB2 and erbB4 are presynaptically localized within C boutons, suggesting that NRG1-based retrograde signaling may occur in this type of synapse. In most of the cranial nuclei, MNs display the same pattern of NRG1 distribution as that observed in spinal cord MNs. Conversely, MNs in oculomotor nuclei, which are spared in amyotrophic lateral sclerosis (ALS), lack both C boutons and SSC-associated NRG1. NRG1 in spinal MNs is developmentally regulated and depends on the maintenance of nerve-muscle interactions, as we show after nerve transection experiments. Changes in NRG1 in C boutons were also investigated in mouse models of MN diseases: i.e., spinal muscular atrophy (SMNΔ7) and ALS (SOD1(G93A)). In both models, a transient increase in NRG1 in C boutons occurs during disease progression. These data increase our understanding of the role of C boutons in MN physiology and pathology.

Mutual regulation of TGF-ß1, TßRII and ErbB receptors expression in human thyroid carcinomas.

The role of EGF and TGF-ß1 in thyroid cancer is still not clearly defined. TGF-ß1 inhibited the cellular growth and migration of follicular (FTC-133) and papillary (B-CPAP) thyroid carcinoma cell lines. Co-treatments of TGF-ß1 and EGF inhibited proliferation in both cell lines, but displayed opposite effect on their migratory capability, leading to inhibition in B-CPAP and promotion in FTC-133 cells, by a MAPK-dependent mechanism. TGF-ß1, TßRII and EGFR expressions were evaluated in benign and malignant thyroid tumors. Both positivity (51.7% and 60.0% and 80.0% in FA and PTC and FTC) and overexpression (60.0%, 77.7% and 75.0% in FA, PTC and FTC) of EGFR mRNA correlates with the aggressive tumor behavior. The moderate overexpression of TGF-ß1 and TßRII mRNA in PTC tissues (61.5% and 62.5%, respectively), counteracted their high overexpression in FTC tissues (100% and 100%, respectively), while EGFR overexpression was similar in both carcinomas. Papillary carcinomas were positive to E-cadherin expression, while the follicular carcinomas lose E-cadherin staining. Our findings of TGF-ß1/TßRII and EGFR overexpressions together with a loss of E-cadherin observed in human follicular thyroid carcinomas, and of increased migration ability MAPK-dependent after EGF/TGF-ß1 treatments in the follicular thyroid carcinoma cell line, reinforced the hypothesis of a cross-talk between EGF and TGF-ß1 systems in follicular thyroid carcinomas phenotype.