Influence of ERBB4 on endocrine therapy of breast cancer
Description
The ligand activated ERBB4 undergoes regulated intracellular proteolysis at the cell surface to release soluble intracellular domain (4ICD). Nuclear 4ICD is an independently signaling protein that functions as a potent estrogen receptor (ER) coactivator. In contrast, my studies indicate that cytosolic 4ICD accumulates in the mitochondria and functions as a proapoptotic BH3 only protein to induce apoptosis of breast tumor cells. Clinical data confirms that cytosolic but not membrane ERBB4 expression in primary human breast tumors is associated with tumor apoptosis, providing a mechanistic explanation for the loss of ERBB4 expression during tumor progression. Recent clinical evidence indicates that loss of ERBB4 expression is an independent marker for tamoxifen resistance. In direct corroboration with clinical observations, I show that suppression of ERBB4 expression in the tamoxifen-sensitive MCF-7 and T47D breast tumor cell lines results in resistance to tamoxifen-induced apoptosis. Furthermore, three independent MCF-7 models of acquired tamoxifen resistance lacked ERBB4 expression. My results clearly indicate that tamoxifen disrupts an estrogen-driven interaction between ER and 4ICD while promoting mitochondrial accumulation of the 4ICD BH3-only protein. Finally, reintroduction of ERBB4, but not ERBB4 with a mutated BH3 domain, restores tamoxifen sensitivity to tamoxifen-resistant TamR cells in a mouse xenograft model. Identification of the ERBB4/4ICD BH3-only protein as a critical mediator of tamoxifen action provides a clinically important role for 4ICD in human cancer and reveals a potential tumor marker to predict patient response to tamoxifen therapy