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SUMOylation of ZFP282 potentiates its positive effect on estrogen signaling in breast tumorigenesis.

ABSTRACT: Estrogen receptor ? (ER?) has critical roles in the development and progression of breast cancer, and the coiled-coil co-activator (CoCoA) is an important ER? co-activator for estrogen-induced gene expression. The small ubiquitin-like modifier (SUMO) pathway is hyperactivated in breast cancer, but the mechanism by which SUMOylation regulates ER?-mediated transcription remains poorly understood. Here, we identified ZFP282 as a CoCoA-binding protein. ZFP282 associates directly with ER? and cooperates synergistically with CoCoA to enhance ER? function. ZFP282 is required for estrogen-induced expression of ER? target genes and estrogen-dependent breast cancer cell growth and tumorigenesis. In addition, we found that ZFP282 is SUMOylated and that SUMOylation positively regulates the co-activator activity of ZFP282 by increasing its binding affinity to ER? and CoCoA, and consequently increasing recruitment of ZFP282-CoCoA complex to the promoter of ER? target genes. These findings reveal essential roles for ZFP282 and its SUMOylation in estrogen signaling and breast tumorigenesis.

SUBMITTER: Yu EJ

PROVIDER: S-EPMC3874449 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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SUMOylation of ZFP282 potentiates its positive effect on estrogen signaling in breast tumorigenesis.

Yu E J EJ Kim S-H SH Kim M J MJ Seo W-Y WY Song K-A KA Kang M-S MS Yang C K CK Stallcup M R MR Kim J H JH

Oncogene 20120917 35

Estrogen receptor α (ERα) has critical roles in the development and progression of breast cancer, and the coiled-coil co-activator (CoCoA) is an important ERα co-activator for estrogen-induced gene expression. The small ubiquitin-like modifier (SUMO) pathway is hyperactivated in breast cancer, but the mechanism by which SUMOylation regulates ERα-mediated transcription remains poorly understood. Here, we identified ZFP282 as a CoCoA-binding protein. ZFP282 associates directly with ERα and coopera ...[more]

PMID: 22986521

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Project description:Limited knowledge of the changes in estrogen receptor (ER) signaling during the transformation of the normal mammary gland to breast cancer hinders the development of effective prevention and treatment strategies. Differences in estrogen signaling between normal human primary breast epithelial cells and primary breast tumors obtained immediately following surgical excision were explored. Transcriptional profiling of normal ER+ mature luminal mammary epithelial cells and ER+ breast tumors revealed significant difference in the response to estrogen stimulation. Consistent with these differences in gene expression, the normal and tumor ER cistromes were distinct and sufficient to segregate normal breast tissues from breast tumors. The selective enrichment of the DNA binding motif GRHL2 in the breast cancer-specific ER cistrome suggests that it may play a role in the differential function of ER in breast cancer. Depletion of GRHL2 resulted in altered ER binding and differential transcriptional responses to estrogen stimulation. Furthermore, GRHL2 was demonstrated to be essential for estrogen-stimulated proliferation of ER+ breast cancer cells. DLC1 was also identified as an estrogen-induced tumor suppressor in the normal mammary gland with decreased expression in breast cancer. In clinical cohorts, loss of DLC1 and gain of GRHL2 expression are associated with breast cancer and are independently predictive for worse survival. This study suggests that normal ER signaling is lost and tumor-specific ER signaling is gained during breast tumorigenesis. Unraveling these changes in ER signaling during breast cancer progression should aid the development of more effective prevention strategies and targeted therapeutics. SIGNIFICANCE STATEMENT: Abnormal estrogen receptor (ER) signaling drives the majority of breast cancers and is targeted by endocrine therapies. However, in normal breast tissue, ER signaling has been demonstrated to promote benign functions such as development and differentiation. Using genomic techniques to characterize ER function in normal breast and breast tumors, this study reveals differential patterns of ER signaling, suggesting that normal ER signaling is lost and tumorigenic ER signaling gained during breast tumor formation. Better understanding of this process can aid the development of improved breast cancer prevention strategies and therapies.

Dataset Information

SUMOylation of ZFP282 potentiates its positive effect on estrogen signaling in breast tumorigenesis.

Publications

SUMOylation of ZFP282 potentiates its positive effect on estrogen signaling in breast tumorigenesis.

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