PELP1: A novel therapeutic target for hormonal cancers

Abstract

Recent studies implicate that the estrogen receptor (ER) coregulator proline-, glutamic acid-, and leucine-rich protein (PELP) 1 as playing critical roles in ER-genomic, ER-nongenomic, and ER-signaling cross talk with growth factor signaling pathways. PELP1 expression is deregulated in hormonal cancers and recent studies further elucidated the molecular mechanisms by which PELP1 regulates hormone therapy response. Although PELP1 is important for normal functions of the ER, the possibility to target ER-PELP1 axis appears to be an effective strategy for preventing hormonal carcinogenesis and therapy resistance. Thus, PELP1 may be useful as prognostic marker for hormonal cancers and PELP1 signaling may be useful to generate targeted therapeutics to overcome hormonal therapy resistance.

Figure 1

Schematic representation of the current understanding of PELP1 signaling pathway. PELP1 appears to function as a scaffolding protein that facilitates formation of various signaling complexes and its expression is deregulated in hormonal cancers. PELP1 regulates multiple signaling pathways including ER-genomic signaling by facilitating epigenetic changes, ER-nongenomic signaling by activating Src-MAPK pathway, local estrogen synthesis via ERRα - aromatase signaling and cell cycle progression via pRb/E2F pathway. PELP1 deregulation in hormonal tumors is likely to contribute to the development of tumorigenesis, metastasis and hormonal independence by activating multiple signaling pathways and by facilitating ER signaling cross talk. Insert in the middle shows PELP1 expression in advanced breast tumors as analyzed by IHC.