Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer

Altres ajuts: This work has been supported by the Community of Madrid (grant S2010/BMD-2303 to GMB), the Breast Cancer Research Foundation (BCRF) to JA. Alba Mota is a predoctoral student supported by a FPU fellowship (Spanish Ministry of Education, Culture and Sport). David Sarrio is a postdoctoral researcher funded by the AECC Scientific Foundation.Around, 30-40% of HER2-positive breast cancers do not show substantial clinical benefit from the targeted therapy and, thus, the mechanisms underlying resistance remain partially unknown. Interestingly, ERBB2 is frequently co-amplified and co-expressed with neighbour genes that may play a relevant role in this cancer subtype. Here, using an in silico analysis of data from 2,096 breast tumours, we reveal a significant correlation between Gasdermin B (GSDMB) gene (located 175 kilo bases distal from ERBB2) expression and the pathological and clinical parameters of poor prognosis in HER2-positive breast cancer. Next, the analysis of three independent cohorts (totalizing 286 tumours) showed that approximately 65% of the HER2-positive cases have GSDMB gene amplification and protein over-expression. Moreover, GSDMB expression was also linked to poor therapeutic responses in terms of lower relapse free survival and pathologic complete response as well as positive lymph node status and the development of distant metastasis under neoadjuvant and adjuvant treatment settings, respectively. Importantly, GSDMB expression promotes survival to trastuzumab in different HER2-positive breast carcinoma cells, and is associated with trastuzumab resistance phenotype in vivo in Patient Derived Xenografts. In summary, our data identifies the ERBB2 co-amplified and co-expressed gene GSDMB as a critical determinant of poor prognosis and therapeutic response in HER2-positive breast cancer

Oral tolerance in antigen induced arthritis (AIA) in rabbits by administration of articular cartilage hydrolysate

La artritis reumatoide es una patología autoinmune caracterizada por inflamación poliarticular, tumefacción e inflamación que afecta a más del 1% de la población mundial. La patobiología de la artritis reumatoide involucra varias poblaciones celulares como linfocitos T, B, macrófagos y fibroblastos, así como una compleja interacción de citoquinas proinflamatorias. Las actuales terapias convencionales y biológicas no siempre funcionan o producen solo una mejora parcial. La tolerancia inmunológica es un mecanismo por el cual el sistema inmune previene la autorreactividad. El objetivo de este estudio piloto fue evaluar la eficacia de péptidos provenientes de un hidrolizado enzimático de cartílago articular extraído del tarso bovino (HCA) para el tratamiento de artritis reumatoide en un modelo de artritis reumatoide (AAE) en conejos. Los animales AAE presentaron inflamación y dolor dentro del primer mes de la inmunización primaria que fue revertida en el grupo AAE + HCA. El grupo control mostró un tejido sinovial normal sin afecciones de ningún tipo. El grupo AAE reveló un proceso inflamatorio severo con hiperplasia sinovial, infiltrado de linfocitos y proliferación vascular. El grupo tratado redujo la inflamación, proliferación linfocítica y neoangiogénesis significativamente. Los conejos artríticos incrementaron significativamente los niveles marcadores inflamatorios como óxido nítrico, interferon γ (INF-γ) y factor de necrosis tumoral α (TNF- α) respecto del control y redujeron significativamente los niveles de interleukina 4 (IL-4). El tratamiento mostró una reducción significativa de óxido nítrico, IFN-γ y TNF-α y un aumento de IL-4. Este trabajo sugiere que esta terapia podría resultar útil en el aspecto clínico y en los parámetros bioquímicos y podría inhibir específicamente la respuesta inmune. Futuros estudios con mayor número de animales y otros parámetros de laboratorio complementarios podrán brindar evidencias en este sentido.Rheumatoid arthritis is an autoimmune disease characterized by polyarticular inflammation, swelling and inflammation that affects more than 1% of the world population. The pathobiology of rheumatoid arthritis involves several cell populations as T lymphocytes, B, macrófagosy fibroblasts, and a complex proinflammatory cytokines interactions. Conventional and biologic therapies do not always work or produce only a partial improvement. Immunological tolerance is a mechanism by which the immune system prevents autoreactivity. The aim of this pilot study was to evaluate the efficacy of peptides from an from articular cartilage hydrolysate extracted of tarsus (HCA) for the treatment of rheumatoid arthritis in a model of rheumatoid arthritis (AAE) in rabbits. AAE animals showed inflammation and pain within de first month of the primary immunization that was reversed in the AAE + HCA group. The control group showed a normal unnaffected synovial tissue. The AAE group revealed an inflamatory process whith synovial hyperplasia, filtering in lymphocytes and vascular proliferation. The treated group decreased significantly inflammation, lymphocyte proliferation and angiogenesis. Arthritic rabbits increased the levels in flammatory markers as nitric oxide, interferon gamma (INF-ɣ) and tumor necrosis factor alpha (TNF-α) compared to control and significantly reduced levels of interleukin 4 (IL-4). The treatment showed a significant reduction of nitricoxide, IFN-gamma and TNF-alpha and an increase in IL-4. This work suggests that this therapy may be useful in the clinical aspect and the biochemical and immune parameters. Future studies with larger numbers of animals and other laboratory parameters may provide additional evidence in this regard.Fil: Abramson, David. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Laboratorio de Biología Osteoarticular, Ingeniería Tisular y Terapias Emergentes; ArgentinaFil: Cabello, Julieta Virginia. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Laboratorio de Biología Osteoarticular, Ingeniería Tisular y Terapias Emergentes; ArgentinaFil: Bumaguin, Gaston E. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Laboratorio de Biología Osteoarticular, Ingeniería Tisular y Terapias Emergentes; ArgentinaFil: Jamin, Alexis. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Laboratorio de Biología Osteoarticular, Ingeniería Tisular y Terapias Emergentes; ArgentinaFil: Vitelli, Ezequiel J.. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Laboratorio de Biología Osteoarticular, Ingeniería Tisular y Terapias Emergentes; ArgentinaFil: Zingoni, Leandro. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Laboratorio de Biología Osteoarticular, Ingeniería Tisular y Terapias Emergentes; ArgentinaFil: Sarrio, Leandro. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Laboratorio de Biología Osteoarticular, Ingeniería Tisular y Terapias Emergentes; ArgentinaFil: Feldman, Sara. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Laboratorio de Biología Osteoarticular, Ingeniería Tisular y Terapias Emergentes; ArgentinaFil: Cointry, Gustavo Roberto. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Centro de Estudios de Metabolismo Fosfocálcico; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas

Purpose: Classic lobular carcinomas (CLC) account for 10% to 15% of all breast cancers. At the genetic level, CLCs show recurrent physical loss of chromosome16q coupled with the lack of E-cadherin (CDH1 gene) expression. However, little is known about the putative therapeutic targets for these tumors. The aim of this study was to characterize CLCs at the molecular genetic level and identify putative therapeutic targets. Experimental Design: We subjected 13 cases of CLC to a comprehensive molecular analysis including immunohistochemistry for E-cadherin, estrogen and progesterone receptors, HER2/ neu and p53; high-resolution comparative genomic hybridization (HR-CGH); microarray-based CGH (aCGH); and fluorescent and chromogenic in situ hybridization for CCND1 and FGFR1. Results: All cases lacked the expression of E-cadherin, p53, and HER2, and all but one case was positive for estrogen receptors. HR-CGH revealed recurrent gains on 1q and losses on 16q (both, 85%). aCGH showed a good agreement with but higher resolution and sensitivity than HR-CGH. Recurrent, high level gains at 11q13 (CCND1) and 8p12-p11.2 were identified in seven and six cases, respectively, and were validated with in situ hybridization. Examination of aCGH and the gene expression profile data of the cell lines, MDA-MB-134 and ZR-75-1, which harbor distinct gains of 8p12-p11.2, identified FGFR1 as a putative amplicon driver of 8p12-p11.2 amplification in MDA-MB-134. Inhibition of FGFR1 expression using small interfering RNA or a small-molecule chemical inhibitor showed that FGFR1 signaling contributes to the survival of MDA-MB-134 cells. Conclusions: Our findings suggest that receptor FGFR1 inhibitors may be useful as therapeutics in a subset of CLCs

Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer

Altres ajuts: This work has been supported by the Community of Madrid (grant S2010/BMD-2303 to GMB), the Breast Cancer Research Foundation (BCRF) to JA. Alba Mota is a predoctoral student supported by a FPU fellowship (Spanish Ministry of Education, Culture and Sport). David Sarrio is a postdoctoral researcher funded by the AECC Scientific Foundation.Around, 30-40% of HER2-positive breast cancers do not show substantial clinical benefit from the targeted therapy and, thus, the mechanisms underlying resistance remain partially unknown. Interestingly, ERBB2 is frequently co-amplified and co-expressed with neighbour genes that may play a relevant role in this cancer subtype. Here, using an in silico analysis of data from 2,096 breast tumours, we reveal a significant correlation between Gasdermin B (GSDMB) gene (located 175 kilo bases distal from ERBB2) expression and the pathological and clinical parameters of poor prognosis in HER2-positive breast cancer. Next, the analysis of three independent cohorts (totalizing 286 tumours) showed that approximately 65% of the HER2-positive cases have GSDMB gene amplification and protein over-expression. Moreover, GSDMB expression was also linked to poor therapeutic responses in terms of lower relapse free survival and pathologic complete response as well as positive lymph node status and the development of distant metastasis under neoadjuvant and adjuvant treatment settings, respectively. Importantly, GSDMB expression promotes survival to trastuzumab in different HER2-positive breast carcinoma cells, and is associated with trastuzumab resistance phenotype in vivo in Patient Derived Xenografts. In summary, our data identifies the ERBB2 co-amplified and co-expressed gene GSDMB as a critical determinant of poor prognosis and therapeutic response in HER2-positive breast cancer