ERBB4 is a unique member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. In contrast to the other three members of the EGFR family (i.e., EGFR, ERBB2, and ERBB3), which are associated with aggressive forms of human cancers, ERBB4 expression seems to be selectively lost in tumors with aggressive phenotypes. Consistent with this observation, we have shown that ERBB4 induces apoptosis when reintroduced into breast cancer cell lines or when endogenous ERBB4 is activated by a ligand. Upon ligand activation, membrane ERBB4 undergoes proteolytic processing to release the ERBB4 intracellular domain (4ICD). We show that cleavage of endogenous ERBB4 is critical for ERBB4 apoptotic activity and results in mitochondrial accumulation of the 4ICD followed by cytochrome c efflux and activation of cellular caspases. We further show that 4ICD harbors a functional BH3 domain and ERBB4 functions as a unique proapoptotic member of BCL-2 family. Clinically, cytosolic but not membrane ERBB4/4ICD expression in primary human breast tumors was associated with tumor apoptosis, providing a mechanistic explanation for the loss of ERBB4 expression during tumor progression. Alternatively, we have shown that ERBB4/4ICD is a transcriptional coactivator and 4ICD directly interacts with estrogen receptor (ER) to selectively potentiate estrogen regulated gene expression. Furthermore ERBB4 itself is an estrogen regulated gene and 4ICD contributes to estrogen-induced proliferation of ER positive breast cancer cells. These observations are corroborated clinically where ERBB4 is significantly associated with ER expression in primary breast tumors. Strikingly, the vast majority of patients with tumors coexpressing ERBB4 and ER respond to endocrine therapy whereas 40% of patients expressing ER alone succumb to their disease. Based upon these clinical results we tested the hypothesis that ERBB4 regulates tumor response to endocrine therapy. In support of this hypothesis we found that in three independent preclinical cell models, tamoxifen resistance was associated with the suppression of ERBB4 expression. Furthermore, reintroduction of ERBB4 in a tamoxifen resistant cell line reestablished tamoxifen sensitivity. Tamoxifen treatment of breast cancer cells resulted in translocation of the 4ICD BH3-only protein to the mitochondria and activation of apoptosis. The molecualr mechanisms underlying this unique mode of action for tamoxifen will be described. We propose that ERBB4 represents an important tumor marker predicting therapeutic response of breast cancer patients undergoing endocrine therapy.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA