Role of PY Motif Containing Protein, WBP-2 in ER, PR Signaling and Breast Tumorigenesis

Our data demonstrates that WBP-2 is recruited onto the hormone responsive promoters in the presence of hormone and it specifically enhances the transactivation functions of PR and ER. Our data also demonstrates that WBP-2 contains an intrinsic activation domain and the cPPXY of WBP-2 is essential for its coactivation and intrinsic activation functions. Our data also demonstrates that the WBP-2 binding protein, YAP1 enhances PR and ER transactivation but YAP1s coactivation function is absolutely dependent on WBP-2. Furthermore, cPPXY motif of WBP-2 and WW-domain of YAP1 is required for YAP1 to work as a transcriptional coactivator. Additionally, our data also indicate that the coactivation functions of WBP-2 and YAP1 are suppressed by WWOX1, suggesting that WWOX1 may regulates the transactivation functions of ER and PR by antagonizing the functions of WBP-2 and YAP1. Taken together our data established the role of WBP-2 and YAP1 as coactivators and WWOX1 as a repressor for ER and PR transactivation pathways. In order to relate these observations to clinical setting, we also analyzed the expression of WBP-2, YAP-1, WWOX1, ER and PR in breast tumors and compared it with that of adjacent normal breast tissue.