Previous data have already shown that high levels Imatinib Mesylate of p130Cas correlate with intrinsic resistance to tamo ifen treatment in a large subset of estrogen receptor positive human breast tumors. Moreover, in human breast cancers overe pression of both HER2 and p130Cas is associated with poor prognosis. Conclusions Overall in this work we demonstrate the involvement of p130Cas in mesenchymal breast cancer cell plasticity, highlighting a new pathway linking p130Cas to Co 2 through c Src and JNK activities. p130Cas is thus emerging as a critical player for onset and progres sion of many aggressive cancers, strengthening its rele vance as an unfavorable prognostic marker and a putative therapeutic target, mostly in combination with high levels of ER, HER2 or Co 2, respectively.

Introduction Rheumatoid arthritis is characterized by inflamed synovial tissue containing a massive infiltration of lym phocytes and macrophages with synovial fibroblast prolif eration. IL 18, an IL 1 family member, is involved in RA pathogenesis. We and others have shown that IL 18 plays an important role in the immune response, in local or systemic angiogenesis, and in monocyte recruit ment. Various sources of IL 18 have been identified in cluding antigen presenting cells, as well as keratinocytes, articular chondrocytes, osteoblasts, and synovial fibro blasts. IL 18, is produced as a biologically inactive precursor protein containing a propeptide domain localized to the cytoplasm. To be activated, pro IL 18 requires cleavage by the IL 1B converting enzyme, which is a member of the aspartate specific cysteine protease family.

Caspase 1 is pro duced as an inactive form. To be activated, its needs to be cleaved into 20 kDa and 10 kDa subunits. Both sub units form heterodimers with interactions with other proteins and are involved in inflammasome formation and activation of inflammatory processes. Active caspase Dacomitinib 1 is located in the plasma membrane, where it cleaves pro IL 18 to IL 18. Caspase 1 and pro IL 18 IL 18 are comple ed to other proteins that are involved in the secretion of IL 18. Caspase 1 is also a critical putative target in patients with cryopyrin associated periodic syndromes. When IL 18 is secreted, it becomes active. IL 18 bioactivity is dependent on both IL 18 and IL 18 binding protein levels. Among various signaling pathways, the mitogen activated protein kinase family, nuclear factor kappa light chain enhancer of activated B cells and janus activated kinase pathways are thought to be critical in RA pathogenesis. All these pathways can be activated by TNF. We previously des cribed ways to regulate TNF induced IL 18 bioactivity in RA synovial fibroblasts by modulation of IL 18 or IL 1BP.