Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A significant proportion of estrogen receptor positive (ER+) breast cancer (BC) initially responds to endocrine therapy but eventually evolves into therapy resistant-BC. TFAP2C (transcription factor AP-2 gamma) is a known regulator of ER activity and high expression of TFAP2C is associated with a decreased response to endocrine therapies. PELP1 is a nuclear receptor coregulator, commonly overexpressed in BC, and its levels are correlated with poorer survival. In this study, we identified PELP1 as a novel interacting protein of TFAP2C. RNA-Seq analysis of PELP1 knockdown BC cells followed by transcription factor motif prediction, pointed to TFAP2C being enriched in PELP1 regulated genes. Gene set enrichment analysis revealed that TFAP2C-PELP1 axis induced a subset of common genes. Reporter gene assays confirmed PELP1 functioning as a coactivator of TFAP2C. Mechanistic studies showed that PELP1-mediated changes in histone methylation contribute to increased expression of the TFAP2C target gene RET. Furthermore, the TFAP2C-PELP1 axis promoted activation of the RET signaling pathway, which contributed to downstream activation of AKT and ERK pathways in ER+BC cells. Concomitantly, knockdown of PELP1 attenuated these effects mediated by TFAP2C. Overexpression of TFAP2C contributed to increased cell proliferation and therapy resistance in ER+ BC models, while knock down of PELP1 mitigated these effects. Utilizing ZR75-TFAP2C xenografts with or without PELP1 knockdown, we provided genetic evidence that endogenous PELP1 is essential for TFAP2C driven BC progression in vivo. Collectively, our studies demonstrated that PELP1 plays a critical role in TFAP2C transcriptional and tumorigenic functions in breast cancer and blocking the PELP1-TFAP2C axis could have utility for treating therapy resistance.
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PMID:Interaction of transcription factor AP-2 gamma with proto-oncogene PELP1 promotes tumorigenesis by enhancing RET signaling. 3326 40


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