Endocrine-Related Cancer

AR signaling effects in breast cancer subtypes. (A) ER-positive/AR-positive breast cancer: (1) AR directly inhibits ER target genes. (2) AR competes with ER for binding on ERE. (3) AR binds and sequesters TF. (4) AR upregulates ERβ receptors. (5) AR induces direct downregulation of cyclin D1 gene expression. (B) TN/LAR BC: AR drives tumor progression. (C) ERneg/HER2pos/ARpos BC: (1) AR directly upregulates WNT7B, which acts on WNT/β-CATENIN, stimulating HER3 gene transcription with subsequent HER3/HER2 heterodimerization and modulation of PI3K/AKT pathway. (2) HER2/HER3 heterodimers activate PI3K/AKT pathway, which phosphorylates MAD1, promoting its degradation and dissociation from Max with subsequent MYC-MAX heterodimerization and access to transcriptional sites. (3) AR induces dissociation of repressor transcription factor 7-like 2 (TCF7L2) from the pioneer transcription factor of AR, FOXA1, promoting AR target gene MYC transcription. (4) AR induces ErbB2 expression, which activates ERK with consequent cell proliferative effect.