ErbB2 Receptor in Breast Cancer: Implications in Cancer Cell Migration, Invasion and Resistance to Targeted Therapy

Overexpression of ErbB2 is found in several types of human carcinomas. In breast tumors, ErbB2 overexpression is detected in up to 20% of patients. Breast cancers in with amplification of ErbB2 are characterized by rapid tumor growth, lower survival rate and increased disease progression. The molecular mechanisms underlying the oncogenic action of ErbB2 involve a complex signaling network that tightly regulates malignant cell migration and invasion and hence metastatic potential. Recent efforts have been made to identify gene expression signatures of ErbB2-positive invasive breast cancers that may represent important mediators of ErbB2-induced tumorigenesis and metastatic progression. In this chapter, we will discuss the canonical ErbB2 signaling pathways responsible for tumor growth and dissemination along with newly identified mediators such as adaptor protein p130Cas and miRNAs. From a therapeutic point of view, the treatment with anti-ErbB2 monoclonal antibody trastuzumab has greatly improved the outcomes of patients with ErbB2 aggressive cancer. Nevertheless, de novo and acquired resistance to trastuzumab therapy still represent a major clinical problem. In the second part of the chapter, we will provide an overview of the mechanisms so far implicated in the onset of resistance to targeted therapy and of the new strategies to overcome resistance

TRK fusion positive cancers:From first clinical data of a TRK inhibitor to future directions

Genetic alterations of neurotrophic tropomyosin or tyrosine receptor kinase (NTRK) 1/2/3 genes generate TRK fusion proteins have been reported in a variety of adult and child cancers from diverse cell/tissue lineages. Larotrectinib, a tumour-agnostic TRK inhibitor, has shown remarkable efficacy in a novel "basket" study which has enrolled patients from infants to elderly with different TRK fusion-positive cancers. In this review, we focus on the challenges and expectations on the development of "tumour-agnostic" targeted therapies in rare malignancies.</p

TRK fusion positive cancers:From first clinical data of a TRK inhibitor to future directions

Genetic alterations of neurotrophic tropomyosin or tyrosine receptor kinase (NTRK) 1/2/3 genes generate TRK fusion proteins have been reported in a variety of adult and child cancers from diverse cell/tissue lineages. Larotrectinib, a tumour-agnostic TRK inhibitor, has shown remarkable efficacy in a novel "basket" study which has enrolled patients from infants to elderly with different TRK fusion-positive cancers. In this review, we focus on the challenges and expectations on the development of "tumour-agnostic" targeted therapies in rare malignancies.</p

Dysregulation of Blimp1 transcriptional repressor unleashes p130Cas/ErbB2 breast cancer invasion

ErbB2 overexpression is detected in approximately 20% of breast cancers and is correlated with poor survival. It was previously shown that the adaptor protein p130Cas/BCAR1 is a crucial mediator of ErbB2 transformation and that its overexpression confers invasive properties to ErbB2-positive human mammary epithelial cells. We herein prove, for the first time, that the transcriptional repressor Blimp1 is a novel mediator of p130Cas/ErbB2-mediated invasiveness. Indeed, high Blimp1 expression levels are detected in invasive p130Cas/ErbB2 cells and correlate with metastatic status in human breast cancer patients. The present study, by using 2D and 3D breast cancer models, shows that the increased Blimp1 expression depends on both MAPK activation and miR-23b downmodulation. Moreover, we demonstrate that Blimp1 triggers cell invasion and metastasis formation via its effects on focal adhesion and survival signaling. These findings unravel the previously unidentified role that transcriptional repressor Blimp1 plays in the control of breast cancer invasiveness

Dysregulation of Blimp1 transcriptional repressor unleashes p130Cas/ErbB2 breast cancer invasion

ErbB2 overexpression is detected in approximately 20% of breast cancers and is correlated with poor survival. It was previously shown that the adaptor protein p130Cas/BCAR1 is a crucial mediator of ErbB2 transformation and that its overexpression confers invasive properties to ErbB2-positive human mammary epithelial cells. We herein prove, for the first time, that the transcriptional repressor Blimp1 is a novel mediator of p130Cas/ErbB2-mediated invasiveness. Indeed, high Blimp1 expression levels are detected in invasive p130Cas/ErbB2 cells and correlate with metastatic status in human breast cancer patients. The present study, by using 2D and 3D breast cancer models, shows that the increased Blimp1 expression depends on both MAPK activation and miR-23b downmodulation. Moreover, we demonstrate that Blimp1 triggers cell invasion and metastasis formation via its effects on focal adhesion and survival signaling. These findings unravel the previously unidentified role that transcriptional repressor Blimp1 plays in the control of breast cancer invasiveness

Identification of p130Cas/ErbB2-dependent invasive signatures in transformed mammary epithelial cells

Understanding transcriptional changes during cancer progression is of crucial importance to develop new and more efficacious diagnostic and therapeutic approaches. It is well known that ErbB2 is overexpressed in about 25% of human invasive breast cancers. We have previously demonstrated that p130Cas overexpression synergizes with ErbB2 in mammary cell transformation and promotes ErbB2-dependent invasion in three-dimensional (3D) cultures of human mammary epithelial cells. Here, by comparing coding and non-coding gene expression profiles, we define the invasive signatures associated with concomitant p130Cas overexpression and ErbB2 activation in 3D cultures of mammary epithelial cells. Specifically, we have found that genes involved in amino acids synthesis (CBS, PHGDH), cell motility, migration (ITPKA, PRDM1), and angiogenesis (HEY1) are upregulated, while genes involved in inflammatory response (SAA1, S100A7) are downregulated. In parallel, we have shown that the expression of specific miRNAs is altered. Among these, miR-200b, miR-222, miR-221, miR-R210, and miR-424 are upregulated, while miR-27a, miR-27b, and miR-23b are downregulated. Overall, this study presents, for the first time, the gene expression changes underlying the invasive behavior following p130Cas overexpression in an ErbB2 transformed mammary cell model

La Scienza e l'immaginario

L’attività di divulgazione della cultura scientifica ha un ruolo fondamentale sulla società, sia in termini di applicazioni innovative che di pianificazione dell’ambiente. I ricercatori dell’IAS-CNR di Capo Granitola operano da anni nell’ambito della diffusione della cultura scientifica, attraverso processi complessi e percorsi di divulgazione in partnership con istituti scolastici del territorio, realizzando attività seminariali, convegni direttamente nelle scuole, nonché visite didattiche guidate degli alunni nei laboratori dell’Istituto ed esperimenti interdisciplinari sull’ambiente marino. Tali processi divulgativi si sono sviluppati creando numerosi percorsi, in maniera per certi aspetti analoga a quella per cui dalla mescolanza dei tre colori fondamentali si è in grado di ottenere un numero pressoché illimitato di tinte diverse. Lo scopo di questa “mescolanza” è stato quello di ottenere un ventaglio di competenze e strumentazioni che consentissero di indagare i differenti aspetti dell’ecosistema marino da diversi punti di vista ed in maniera sinergica, tale da restituire un quadro il più ricco possibile di “tinte” e particolari. (Scienza e arte di Salvatore Mazzola) La Scienza e l'immaginario di Angela Cuttitta. Il progetto “La Scienza e l’Immaginario” nasce dalla collaborazione tra l’IAS - CNR di Capo Granitola e l’Accademia di Belle Arti di Palermo, che attraverso un approccio multidisciplinare ha voluto sperimentare l’unione tra il mondo scientifico e quello artistico, mettendo i giovani artisti, attraverso proiezioni e seminari scientifici, nelle condizioni di scoprire il mondo dell’ambiente marino e degli ecosistemi in esso presenti. Il progetto è nato dalla consapevolezza di come sia necessario operare sul piano della diffusione e divulgazione della cultura scientifica nei più vasti contesti sociali, a partire dall’ambito scolastico. Le azioni divulgative mirano, infatti, a diffondere la conoscenza dei processi geologici, chimico-fisici, climatici e biologici in modo pervasivo, non limitato a singole categorie/settori. La funzione strategica di tali azioni è quella di stimolare idee ed iniziative nonché di sviluppare una maggiore sensibilità nei confronti dei fenomeni che ci circondano, quale presupposto essenziale per una corretta programmazione politico-gestionale. Lo spirito che ha mosso tutte gli attori del progetto è stato quello di sensibilizzare gli studenti nei confronti della tutela delle risorse marine proprie del loro territorio e di sviluppare e promuovere la cultura come volano dello sviluppo sostenibile, della pace e dell’integrazione sociale, in armonia con quanto indicato dal Consiglio Europeo di Lisbona 2000. Grazie al lavoro di docenti e di ricercatori, l’arte come forma espressiva si è rivelata uno strumento valido e innovativo di divulgazione della cultura scientifica e ha portato alla creazione di suggestioni sui ragazzi che hanno percepito e realizzato forme e armonie espresse in questa mostra. L’impegno per questa manifestazione rappresenta, quindi, un appuntamento importante con le forze vive siciliane nel campo delle scienze del mare segnatamente ad esperti di biologia, chimica, fisica ed al mondo fantastico dell’arte, al fine di esprimere con le varie tecniche pittoriche un momento di riflessione culturale

p130Cas/BCAR1 scaffold protein in tissue homeostasis and pathogenesis

BCAR1 (also known as p130Cas/BCAR1) is an adaptor protein that belongs to the CAS family of scaffold proteins. In the past years, increasing evidence has demonstrated the ability of p130Cas/BCAR1 to activate signaling originating from mechanical stimuli, cell–extracellular matrix (ECM) adhesion and growth factor stimulation cascades during normal development and disease in various biological models. In this review we will specifically discuss the more recent data on the contribution of p130Cas/BCAR1 in the regulation of tissue homeostasis and its potential implications in pathological conditions

The storm of NGS in NSCLC diagnostic-therapeutic pathway: How to sun the real clinical practice

The increasing number of approved drugs along with next generation sequencing (NGS) technologies look out as potential revolution of biomolecular characterization of non-small-cell lung cancer (NSCLC). Nevertheless, several aspects impact on success rate of NGS in clinical practice: a multidisciplinary approach and thorough knowledge of strengths and limits of each technologic diagnostic tool are required. Crucial preliminary step is the selection of the best available sample before testing, aware of clinical condition and setting of disease. Genomic data should be than integrated in the clinical context and matched with available therapeutic options; Molecular Tumor Boards (MTB) are worldwide emerging interdisciplinary groups implemented to transfer the impact of precision medicine in clinical practice. In order to guarantee equity in treatment, these considerations should find their application widely and rapidly. Aim of this review is offering an overview of emerging biomarkers, relative upcoming targeted drugs, and new diagnostic chances with an authors' perspective about a real-life diagnostic-therapeutic algorithm useful for daily clinical practice