Estrogen Receptor α–Negative Breast Cancer Tissues Express Significant Levels of Estrogen-Independent Transcription Factors, ERβ1 and ERβ5: Potential Molecular Targets for Chemoprevention

ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor’s ligand-independent transactivation domain. Co-immunoprecipitation with truncated estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in estrogen receptor positive breast cancer.

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Cooperative Coactivation of Estrogen Receptor α in ZR-75 Human Breast Cancer Cells by SNURF and TATA-binding Protein

Journal of Biological Chemistry ◽

10.1074/jbc.m109021200 ◽

2001 ◽

Vol 277 (4) ◽

pp. 2485-2497 ◽

Cited By ~ 27

Author(s):

Bradley Saville ◽

Hetti Poukka ◽

Mark Wormke ◽

Olli A. Jänne ◽

Jorma J. Palvimo ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Cells ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Binding Protein ◽

Estrogen Receptor Α ◽

Tata Binding Protein ◽

Human Breast Cancer Cells ◽

Human Breast

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AKT Alters Genome-Wide Estrogen Receptor α Binding and Impacts Estrogen Signaling in Breast Cancer

Molecular and Cellular Biology ◽

10.1128/mcb.00799-08 ◽

2008 ◽

Vol 28 (24) ◽

pp. 7487-7503 ◽

Cited By ~ 72

Author(s):

Poornima Bhat-Nakshatri ◽

Guohua Wang ◽

Hitesh Appaiah ◽

Nikhil Luktuke ◽

Jason S. Carroll ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Binding Sites ◽

Transforming Growth Factor ◽

Cell Types ◽

Estrogen Receptor Α ◽

Estrogen Signaling ◽

Primary Tumors ◽

Genome Wide ◽

Extracellular Signal

ABSTRACT Estrogen regulates several biological processes through estrogen receptor α (ERα) and ERβ. ERα-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERα binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERα binding sites, respectively, with ∼60% overlap. In both cell types, ∼40% of estrogen-regulated genes associate with ERα binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor β (TGF-β), NF-κB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-β treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERα DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERα binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERα-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERα-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.

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