THE CHILDRENS HOSPITAL LOS ANGELES
Inflammatory bowel diseases are associated with increased risk of early-onset colorectal cancer, incurring great cost both economically and in patient morbidity and mortality. Intensive research has been focused on identifying signaling pathways which may be targets of therapy or chemoprevention in high-risk groups. One candidate molecule is ErbB-4, the most recently described member of the EGFR-related ErbB family of tyrosine kinase growth factor receptors. ErbB-4 is expressed in mammalian tissues as up to four distinct isoforms, and is likely to participate in regulatory mechanisms distinct from those of other ErbB family members. Recent reports have shown ErbB-4 expression in colorectal carcinomas and a possible association with more aggressive disease, though the mechanisms underlying these data are unknown. The parent project for this award is K01 DK077956, “The role of ErbB-4 in inflammation-induced colon carcinogenesis.” It is designed to test the hypothesis that ErbB-4 isoforms promote chronic inflammation induced colon carcinogenesis through increased cell survival, proliferation, and/or migration in the inflammatory environment. The overall parent project Aims are to (1) test ErbB-4 expression in murine AOMDSS colon carcinogenesis, (2) identify ErbB-4 isoforms which promote cellular transformation in vitro, and (3) determine the ability of ErbB-4 isoforms to promote tumor formation in vivo using allograft or xenograft assays. Progress on the first two Aims identified two ErbB-4 isoforms which are both expressed in AOM/ DSS tumors and promote cellular transformation in vitro. Thus, this American Recovery and Reinvestment Act of 2009 (ARRA) administrative supplemental project focuses on testing the ability of those isoforms to promote tumor formation in vivo as planned for the original Aim 3. We are (A) determining the ability of intestinal epithelial cells overexpressing ErbB-4 (JM-a/CYT-2 and JM-b/CYT-2) to establish tumors in an allograft model, and (B) testing ErbB-4's ability to modulate tumor formation in vivo in cooperation with other oncogenes. These studies are expected to clarify the role of ErbB-4 in colitis-associated carcinogenesis, and will potentially identify novel avenues of therapy and chemoprevention based on the activity of specific isoforms.