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Fig. 5 | Breast Cancer Research

Fig. 5

From: HER4 expression in estrogen receptor-positive breast cancer is associated with decreased sensitivity to tamoxifen treatment and reduced overall survival of postmenopausal women

Fig. 5

Suggested 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 inhibited

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