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Yes-associated protein (YAP) has been shown to positively regulate p53 family members and to be negatively regulated by the AKT proto-oncogene product in promoting apoptosis. On the basis of this function and its location at 11q22.2, a site of frequent loss of heterozygosity (LOH) in breast cancer, we investigated whether YAP is a tumor suppressor in breast. Examination of tumors by immunohistochemistry demonstrated significant loss of YAP protein. LOH analysis revealed that protein loss correlates with specific deletion of the YAP gene locus. Functionally, short hairpin RNA knockdown of YAP in breast cell lines suppressed anoikis, increased migration and invasiveness, inhibited the response to taxol and enhanced tumor growth in nude mice. This is the first report indicating YAP as a tumor suppressor, revealing its decreased expression in breast cancer as well as demonstrating the functional implications of YAP loss in several aspects of cancer signaling.

Pancreatic ductal adenocarcinoma is a devastating disease, characterized by a rapid progression and poor treatment response. Using gene expression profiling of pancreatic cancer tissues, we previously identified periostin as a potential diagnostic and therapeutic target. In this study, we report the overexpression of periostin in a larger set of pancreatic cancer tissues and show that although the periostin transcript is exclusively expressed in tumour cells, the protein product is only detected in the extracellular matrix adjacent to cancer cells. Using an enzyme-linked immunosorbent assay (ELISA) assay, we show significantly increased levels of periostin in the sera of pancreatic cancer patients compared to non-cancer controls. We demonstrate that periostin promotes the invasiveness of tumour cells by increasing the motility of cells without inducing expression of proteases, and enhances the survival of tumour cells exposed to hypoxic conditions. At the molecular level, we provide evidence that the alpha(6)beta(4) integrin complex acts as the cell receptor of periostin in pancreatic cancer cells and that interaction promotes phosphorylation of focal adhesion kinase (FAK) and protein kinase B (AKT) though activation of the PI3 kinase pathway, but not the RAS/MEK/ERK pathway. These findings suggest an important role of periostin in pancreatic cancer and provide a rationale to study periostin for diagnostic and therapeutic applications.

Sperm-associated antigen 1 (SPAG1) was recently identified in a rare form of infertility where anti-SPAG1 antibodies derived from the serum of an infertile woman were reported to cause sperm agglutination. Except for its expression and potential role in spermatogenesis, the function of SPAG1 is completely unknown. The unexpected finding of high levels of SPAG1 expression in pancreatic adenocarcinoma compared to normal pancreatic tissue in our previous cDNA array experiments prompted us to look in more detail at the expression and role of this gene in a panel of normal and malignant human tissues as well as in a larger series of pancreatic cancer specimens. We have generated an SPAG1-specific monoclonal antibody and showed high levels of SPAG1 protein in testis and in a large proportion of pancreatic ductal adenocarcinomas (PDAC). In the latter, SPAG1 expression was predominantly cytoplasmic and confined to malignant cells. Furthermore, the extent and intensity of SPAG1 expression was shown to be associated with stage and tumour nodal status, while analysis of precursor lesions, pancreatic intraepithelial neoplasias (PanINs), demonstrated its increased immunoreactivity with increasing PanIN grade, suggesting that SPAG1 is a novel marker of PDAC progression. Immunocytochemical analysis demonstrated colocalization of SPAG1 with microtubules, and their association was confirmed by co-immunoprecipitation; subsequent motility assays further substantiated a potential role of SPAG1 in cancer cell motility. Combined with the finding of its early expression in PDAC development, our data suggest that SPAG1 could contribute to the early spread and poor prognosis of pancreatic adenocarcinoma.