The estrogen receptor-interacting protein HPIP increases estrogen-responsive gene expression through activation of MAPK and AKT

Estrogen receptors (ER alpha and ER beta) are estrogen-regulated transcription factors that play important roles in the development and progression of breast cancer. The biological function of ERs has been shown to be modulated by ER-interacting proteins. However, the ER-interacting proteins that not only activate MAPK and AKT, two important growth regulatory protein kinases, but also increase growth related estrogen-responsive gene expression remain unknown. Here, we report that hematopoietic PBX-interacting protein (HPIP) interacts both with ER alpha and with ER beta, and increases ER alpha target gene expression through activation of MAPK and AKT and enhanced ER alpha phosphorylation. ER beta inhibits ER alpha target gene expression, possibly by competition of ER beta with ER alpha for binding to HPIP, and by a decrease in available ER alpha for HPIP binding through the interaction of ER beta with ER alpha. Furthermore, HPIP increases breast cancer cell growth. These data suggest that HPIP may be an important regulator in ER signaling and that the relative ratio of ER beta to ER alpha may be important for HPIP function. (c) 2008 Elsevier B.V. All rights reserved.