Anterior Gradient Homolog 2 (AGR2) is expressed by the normal intestine and by most human adenocarcinomas, including those derived from the esophagus, pancreas, lung, breast, ovary, and prostate. Xenografts of human adenocarcinoma cell lines in nude mice previously demonstrated that AGR2 supports tumor growth. In addition, AGR2 is able to induce in vitro a transformed phenotype in fibroblast and epithelial cell lines. The mechanism underlying the growth promoting effects of AGR2 is unknown. The present study shows that AGR2 induces expression of amphiregulin (AREG), a growth promoting EGFR ligand. Induced AREG expression in adenocarcinoma cells is able to rescue the transformed phenotype that is lost when AGR2 expression is reduced. Additional experiments demonstrate that AGR2 induction of AREG is mediated by activation of the Hippo signaling pathway co-activator, YAP1. Thus AGR2 promotes growth by regulating the Hippo and EGF receptor signaling pathways. Anterior Gradient Homolog 2 (AGR2)2 encodes a 17 kDa protein that is highly conserved in vertebrates. AGR2 was first described in Xenopus laevis, where its expression is responsible for the development of a glandular organ called the cement gland (1). A significant role in tissue regeneration was established for AGR2 in salamanders where it functions in nerve-dependent limb regeneration (2). AGR2 is also expressed by secretory cells in the normal murine intestine (3). In humans, enhanced AGR2 expression was first described in breast cancer, which was followed by similar observations in most human adenocarcinomas, including those derived from the esophagus, pancreas, lung, ovary, and prostate (4 -11). Both in vitro and in vivo studies demonstrated that AGR2 promotes tumor growth and metastasis (3,6,12). In adenocarcinoma cell lines and nontransformed fibroblasts, AGR2 induces cell proliferation and anchorage-independent growth in soft agar. Human adenocarcinoma cell lines grown in vivo as mouse xenografts result in smaller tumors when AGR2 expression is reduced (3, 6). In vitro studies examining cell migration suggested that AGR2 may function in a non-cell autonomous fashion (3).The mechanisms responsible for AGR2 effects on growth and transformation are unknown. AGR2 expression in humans is restricted to epithelial cells, for which the EGF signaling pathway serves a regulatory role in controlling cell growth. The present study tested the hypothesis that AGR2 affects cell signaling, and potentially that of the EGFR pathway, which has established significance in epithelial cancers. EXPERIMENTAL PROCEDURESCell Lines-H460 lung adenocarcinoma cells obtained from Dr. David Beer (University of Michigan, Ann Arbor, MI) were previously known as SEG-1 and was the focus of a previous publication (3). A recent report revealed that SEG-1 cells are actually H460 lung adenocarcinoma cells (13). The H460 cells used in this study were reassessed by Winand Dinjens, Erasmus Medical Center, Rotterdam, the Netherlands using the Powerplex 16 TM system (Promega Corp., Madison, WI) to...

Program monitoring and evaluation (M&E) has the potential to be a cornerstone of health systems strengthening and of evidence-informed implementation and scale-up of HIV-related services in resource-limited settings. We discuss common challenges to M&E systems used in the rapid scale-up of HIV services as well as innovations that may have relevance to systems used to monitor, evaluate, and inform health systems strengthening. These include (1) Web-based applications with decentralized data entry and real-time access to summary reporting; (2) timely feedback of information to site and district staff; (3) site-level integration of traditionally siloed program area indicators; (4) longitudinal tracking of program and site characteristics; (5) geographic information systems; and (6) use of routinely collected aggregate data for epidemiologic analysis and operations research. Although conventionally used in the context of vertical programs, these approaches can form a foundation on which data relevant to other health services and systems can be layered, including prevention services, primary care, maternal-child health, and chronic disease management. Guiding principles for sustainable national M&E systems include country-led development and ownership, support for national programs and policies, interoperability, and employment of an open-source approach to software development.