ERBB4 is over-expressed in human colon cancer and enhances cellular transformation

Abstract

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 overexpression 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 overexpression 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.

Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer

“…43,44 Moreover, it has been considered to mediate acquired resistance to chemotherapy. 36 Consistently, we found that inhibition of ERBB4 enhanced colon cancer cells apoptosis in response to L-OHP.…”

HER4 isoform CYT2 and its ligand NRG1III are expressed at high levels in human colorectal cancer

“…In addition, the overexpression or mutation of HER3 is associated with malignant cell growth, contributing to enhanced tumor progression and poor patient outcomes (8). There are potentially oncogenic ERBB4 mutations in non-small cell lung cancer (9), and it has been reported that HER4 is overexpressed in human colon cancer and enhances cellular transformation (10). In addition, HER4 promotes breast cancer cell proliferation, mediates acquired resistance to ERBB2 inhibitors and may serve as a prognostic marker in patients with breast cancer (11)(12)(13)(14).…”

ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer

“…Besides direct EGFR signaling associated genes, the most frequent mutations observed in CRC cell lines and cases were ATM, SMAD4, KDR, ErBB4 and FBXW7, as reported by others for CRC before [57, 58]. Indeed, SMAD4, ErBB4 and FBXW7 mutations appear to confer treatment resistance to Cetuximab [5].…”