Loss of beta4 integrin subunit reduces the tumorigenicity of MCF7 mammary cells and causes apoptosis upon hormone deprivation.

PURPOSE: The alpha6beta4 integrin, a laminin receptor, has been implicated from many studies in tumor progression and invasion. We showed that the beta4 integrin subunit associates with the ErbB-2 tyrosine kinase in human mammary carcinoma cell lines and that its overexpression in NIH3T3/ErbB-2-transformed cells causes a constitutive activation of phosphatidylinositol 3-kinase (PI3K), inducing a strong increase of their invasive capacity. In this study, we investigated the biological consequences of interference with the endogenous beta4 integrin subunit expression. EXPERIMENTAL DESIGN: In vitro and in vivo tumor growth and the biochemical consequences of beta4 integrin inactivation were studied in mammary tumor cells by using short hairpin RNA approach. RESULTS: Our data show that tumor growth of mammary tumor cells strictly depends on beta4 expression, confirming the relevance of beta4 protein in these cells. Moreover, interference with beta4 expression significantly reduces endogenous PI3K activity and AKT and mammalian target of rapamycin phosphorylation. Accordingly, with these results and considering that PI3K activity in mammary tumor plays a relevant role in hormone resistance, we asked whether beta4 expression might be relevant for hormone responsiveness in these cells. Data reported indicate that the interference with endogenous beta4 expression, upon hormone deprivation, induces caspase-9 and cytochrome c-mediated apoptosis, which is enhanced upon tamoxifen treatment. On the other hand, the expression of myr-AKT in MCF7 beta4-short hairpin RNA cells rescues the cells from apoptosis in the absence of hormones and upon tamoxifen treatment. CONCLUSIONS: Overall, these results confirm the relevance of beta4 expression in mammary tumors and indicate this integrin as a relevant target for tumor therapy.

Boceprevir or telaprevir in hepatitis C virus chronic infection: The Italian real life experience.

AIM: To check the safety and efficacy of boceprevir/telaprevir with peginterferon/ribavirin for hepatitis C virus (HCV) genotype 1 in the real-world settings. METHODS: This study was a non-randomized, observational, prospective, multicenter. This study involved 47 centers in Italy. A database was prepared for the homogenous collection of the data, was used by all of the centers for data collection, and was updated continuously. All of the patients enrolled in this study were older than 18 years of age and were diagnosed with chronic infection due to HCV genotype 1. The HCV RNA testing was performed using COBAS-TaqMan2.0 (Roche, LLQ 25 IU/mL). RESULTS: All consecutively treated patients were included. Forty-seven centers enrolled 834 patients as follows: Male 64%; median age 57 (range 18-78), of whom 18.3% were over 65; mean body mass index 25.6 (range 16-39); genotype 1b (79.4%); diagnosis of cirrhosis (38.2%); and fibrosis F3/4 (71.2%). The following drugs were used: Telaprevir (66.2%) and PEG-IFN-alpha2a (67.6%). Patients were naïve (24.4%), relapsers (30.5%), partial responders (14.8%) and null responders (30.3%). Overall, adverse events (AEs) occurred in 617 patients (73.9%) during the treatment. Anemia was the most frequent AE (52.9% of cases), especially in cirrhotic. The therapy was stopped for 14.6% of the patients because of adverse events or virological failure (15%). Sustained virological response was achieved in 62.7% of the cases, but was 43.8% in cirrhotic patients over 65 years of age. CONCLUSION: In everyday practice, triple therapy is safe but has moderate efficacy, especially for patients over 65 years of age, with advanced fibrosis, non-responders to peginterferon + ribavirin.