4.7 Article

Interaction of transcription factor AP-2 gamma with proto-oncogene PELP1 promotes tumorigenesis by enhancing RET signaling

期刊

MOLECULAR ONCOLOGY
卷 15, 期 4, 页码 1146-1161

出版社

WILEY
DOI: 10.1002/1878-0261.12871

关键词

breast cancer; coactivator; PELP1; TFAP2C; therapy resistance

类别

资金

  1. VA [I01BX004545]
  2. NCI [P30 CA054174]
  3. Voelcker Fund Young Investigator Award
  4. CPRIT Predoctoral Fellowship
  5. Elsa U. Pardee Foundation [166675-44096]
  6. NIH [R01CA223828]

向作者/读者索取更多资源

PELP1 has been identified as a novel interacting protein of TFAP2C, and both factors regulate a set of genes that affect the progression of breast cancer.
A significant proportion of estrogen receptor-positive (ER+) breast cancer (BC) initially responds to endocrine therapy but eventually evolves into therapy-resistant BC. Transcription factor AP-2 gamma (TFAP2C) 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 (GSEA) revealed that the TFAP2C-PELP1 axis induced a subset of common genes. Reporter gene assays confirmed PELP1 functions as a coactivator of TFAP2C. Mechanistic studies showed that PELP1-mediated changes in histone methylation contributed to increased expression of the TFAP2C target gene RET. Furthermore, the TFAP2C-PELP1 axis promoted the 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 knockdown 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 BC and blocking the PELP1-TFAP2C axis could have utility for treating therapy resistance.

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