ERBB4 is over-expressed in human colon cancer and enhances cellular transformation.
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.
Departments of Medicine and Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA, Department of Surgery, Veterans Affairs Tennessee Valley Health Care System, Nashville, TN 37232, USA.
Christopher S
CS
Williams
Department of Pediatrics, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Jessica K
JK
Bernard
Department of Pediatrics, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Michelle
M
Demory Beckler
Department of Pediatrics, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90089, USA.
Dana
D
Almohazey
Departments of Pathology, Microbiology, and Immunology, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA and.
Mary Kay
MK
Washington
Department of Surgery, Veterans Affairs Tennessee Valley Health Care System, Nashville, TN 37232, USA.
Jesse J
JJ
Smith
Department of Pediatrics, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA, Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA mfrey@usc.edu.
Mark R
MR
Frey
D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D008819:Mice, Nude; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism*; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4; D018631:ras Proteins