The ERBB4
receptor tyrosine kinase promotes colonocyte survival. Herein, we tested whether ERBB4's antiapoptotic signaling promotes transformation and colorectal
tumorigenesis. ERBB4 alterations in a The
Cancer Genome Atlas
colorectal cancer (CRC) data set stratified survival, and in a combined Moffitt
Cancer Center and Vanderbilt Medical Center CRC expression data set, ERBB4 message levels were increased at all
tumor stages. Similarly, western blot and immunohistochemistry on additional CRC tissue banks showed elevated ERBB4
protein in
tumors. ERBB4 was highly expressed in aggressive, dedifferentiated CRC cell lines, and its knockdown in LIM2405 cells reduced anchorage-independent colony formation. In nude mouse xenograft studies, ERBB4 alone was insufficient to induce
tumor establishment of non-transformed mouse colonocytes, but its over-expression in cells harboring Apc(min) and v-Ha-Ras caused a doubling of
tumor size. ERBB4-expressing xenografts displayed increased activation of survival pathways, including
epidermal growth factor receptor and Akt phosphorylation and COX-2 expression, and decreased apoptotic signals. Finally, ERBB4 deletion from mouse intestinal epithelium impaired stem cell replication and in vitro enteroid establishment. In summary, we report that ERBB4 is over-expressed in human CRC, and in experimental systems enhances the survival and growth of cells driven by Ras and/or WNT signaling. Chronic ERBB4 over-expression in the context of, for example,
inflammation may contribute to colorectal
carcinogenesis.
Tumors with high receptor levels are likely to have enhanced cell survival signaling through
epidermal growth factor receptor, PI3K and COX-2. These results suggest ERBB4 as a novel therapeutic target in a subset of CRC.