Fig. 5From: HER4 expression in estrogen receptor-positive breast cancer is associated with decreased sensitivity to tamoxifen treatment and reduced overall survival of postmenopausal womenSuggested mechanism of estrogen receptor (ER) action in the presence and absence of HER4. a HER4 can be processed by a two-step proteolytic activation. First tumor necrosis factor α converting enzyme (TACE) cleaves the extracellular domain, and subsequently y-secretase cleaves the intracellular domain of HER4 (4ICD) which is released into inner cell compartments. If translocated into the nucleus, 4ICD as an ER co-activator enhances the pro-proliferative effects of estrogen. Within an autoloop, 4ICD also enhances the transcription of HER4 itself. b HER4 receptor knockdown eliminates the co-stimulatory activity of 4ICD. As a consequence, appropriately dosed tamoxifen (TAM) can competitively replace the estrogen and binds to the ER. As a result, pro-proliferative activity of the ER is inhibitedBack to article page