The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-α and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP allows for up-regulation of TGF-α, AREG, and EGFR, forming a positive signaling loop to drive cervical cancer cell proliferation. HPV E6 protein, a major etiological molecule of cervical cancer, maintains high YAP protein levels in cervical cancer cells by preventing proteasome-dependent YAP degradation to drive cervical cancer cell proliferation. Results from human cervical cancer genomic databases and an accepted transgenic mouse model strongly support the clinical relevance of the discovered feed-forward signaling loop. Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer.

In this prospective study of endometrial cancer patients younger than age 50 years, 9% were found to carry germline Lynch syndrome-associated mutations. In addition to young age of onset, family history, BMI, and molecular tumor studies can improve the likelihood of identifying a Lynch syndrome-associated germline mutation in MLH1, MSH2, and MSH6.

NY-ESO-1 is a ''cancer-testis'' antigen expressed in epithelial ovarianHLA-DP4 ͉ peptide epitope ͉ tumor recognition ͉ vaccine T here is increasing evidence that the immune system has the ability to recognize tumor-associated antigens expressed in human malignancies and to induce antigen-specific humoral and cellular immune responses to these targets. In epithelial ovarian cancer (EOC), support for the role of immune surveillance of tumors comes from our recent observation indicating that the presence of intraepithelial CD8 ϩ -infiltrating T lymphocytes in tumors is associated with improved survival of patients with the disease (1). Although the majority of women with advanced-stage ovarian cancer respond to first-line chemotherapy, most of these responses are not durable, and Ͼ70% of patients die of recurrent disease within 5 years of diagnosis. Therefore, the development of strategies to enhance the potential of tumor antigen-specific CD8 ϩ T and CD4 ϩ T cells is urgently needed for extending remission rates in this disease. In this regard, cancer-testis antigens, a unique class of antigens that demonstrate high levels of expression in adult male germ cells but generally not in other normal adult tissues and aberrant expression in a variable proportion of a wide range of different cancer types, are promising candidates for immunotherapy. Among cancer-testis antigens, NY-ESO-1 (2) is one of the most spontaneously immunogenic tumor antigens described so far. Previously, we reported that NY-ESO-1 is a promising target for specific immunotherapy of EOC (3).Although the majority of cancer vaccine trials have focused on eliciting antigen-specific CD8 ϩ T cells, a growing body of evidence indicates that CD4 ϩ T cells play a pivotal role in orchestrating these responses. The multiple roles of antigen-specific CD4 ϩ T cells include the provision of help to CD8 ϩ T cells during the primary and secondary immune responses, direct cytolysis, and activation of B cells for production of tumor antigen-specific Abs. Therefore, we have focused on the NY-ESO-1 epitope, ESO 157-170 , a naturally processed helper epitope that is recognized by CD4 ϩ T cells in the context of HLA-DPB1*0401 and *0402 (4), prevalent MHC class II alleles present in Ϸ43-70% of Caucasians. Moreover, the NY-ESO-1 HLA-DP4 epitope has HLA-A2 (ESO 157-165 ) (5) and HLA-A24 (ESO 158-166 ) (6) motifs embedded in its natural sequence. In this study, we evaluated whether active immunization with ESO 157-170 would elicit NY-ESO-1-specific CD4 ϩ and CD8 ϩ T cell responses in ovarian cancer patients with minimal disease burden. In addition, we characterized NY-ESO-1-specific CD8 ϩ and CD4 ϩ T cell receptor (TCR) repertoires in conjunction with functional analysis of vaccine-elicited T cell clones.

The purpose of this study was to understand the characteristics of PDEF protein expression in breast and prostate cancer progression. A polyclonal antibody specific to PDEF was raised and reacted with tissue microarrays consisting of benign breast, in situ ductal, invasive ductal and invasive lobular breast carcinomas. The antibody was also reacted with tissue microarrays including benign prostate, prostate intra-epithelial neoplasias and prostate carcinomas. Increased expression of PDEF was identified in 18%, 50%, 46% and 51% of benign breast tissues, intraductal, invasive ductal and invasive lobular carcinomas, respectively. Importantly, in matched samples of benign breast versus tumor, 90% showed higher expression of PDEF in the tumor tissue. Moreover, in invasive breast carcinomas, increased PDEF expression tended to correlate with Her2/neu over expression. Increased expression of PDEF was also found in 27%, 33% and 40% of benign prostate tissues, PIN samples and prostate adenocarcinomas, respectively. Again, in matching samples of cancer versus benign and cancer versus PIN, 68% and 70% respectively showed increased expression in the malignant tissue. Moreover, PDEF was found to be more highly expressed in tumors with intermediate or high Gleason score compared to low grade tumors (P<0.01). Additionally, R1881 treatment induced PDEF expression in the LNCaP prostate tumor cell line, suggesting regulation of PDEF by androgens in vivo. Together, these results for the first time show frequent increased expression of PDEF protein in breast and prostate tumors and support a role for PDEF in breast and prostate cancer progression.