Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium

Abstract

Pharmacologic blockade of EGFR or the closely related receptor ERBB2 has modest efficacy against colorectal cancers in the clinic. Although the upregulation of ERBB3, a pseudo-kinase member of the EGFR/ERBB family, is known to contribute to EGFR inhibitor resistance in other cancers, its functions in normal and malignant intestinal epithelium have not been defined. We have shown here that the intestinal epithelium of mice with intestine-specific genetic ablation of Erbb3 exhibits no cytological abnormalities but does exhibit loss of expression of ERBB4 and sensitivity to intestinal damage. By contrast, intestine-specific Erbb3 ablation resulted in almost complete absence of intestinal tumors in the Apc Min mouse model of colon cancer. Unlike nontransformed epithelium lacking ERBB3, intestinal tumors lacking ERBB3 had reduced PI3K/ AKT signaling, which led to attenuation of tumorigenesis via a tumor-specific increase in caspase-3-mediated apoptosis. Consistent with the mouse data, which suggest that ERBB3-ERBB4 heterodimers contribute to colon cancer survival, experimentally induced loss of ERBB3 in a KRAS mutant human colon cancer cell line was associated with loss of ERBB4 expression, and siRNA knockdown of either ERBB3 or ERBB4 resulted in elevated levels of apoptosis. These results indicate that the ERBB3 pseudo-kinase has essential roles in supporting intestinal tumorigenesis and suggest that ERBB3 may be a promising target for the treatment of colorectal cancers.

Neuregulin-4 Is a Survival Factor for Colon Epithelial Cells both in Culture and in Vivo

“…In agreement with our results, an anti-apoptotic role for ErbB4 signaling has been demonstrated in several systems, including PC12 cells (28), colorectal cancer cells (29), and breast cancer cells (30). However, it should be noted that this receptor's relationship to cell survival is complex.…”

Toward the Prognostic Significance and Therapeutic Potential of HER3 Receptor Tyrosine Kinase in Human Colon Cancer

“…Our observations are in fact in accordance with previous studies showing the involvement of the HER3 receptor in regulating cell survival. Indeed, Lee and colleagues showed that deletion of HER3 induced a tumor-specific apoptosis in mouse intestinal epithelium (48). In addition, HER3 downregulation in lung cancer cells led to a significant induction of apoptosis (14).…”

TNF-α converting enzyme-mediated ErbB4 transactivation by TNF promotes colonic epithelial cell survival

“…We have recently demonstrated that ErbB4-overexpressing colon epithelial cells acquire the ability to form colonies in soft agar in a cyclooxygenase-2-dependent manner (9). Furthermore, ErbB4 deletion in human colon cancer lines increases apoptosis (20).…”