C-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, PR China.
Oncogene (Impact Factor: 8.46). 04/2010; 29(15):2238-51. DOI: 10.1038/onc.2009.513
Source: PubMed


Estrogen receptors are members of the steroid hormone superfamily of nuclear receptors that act as ligand-activated transcription factors. Similar to other steroid hormone receptors, estrogen receptor alpha (ERalpha) is a substrate for protein kinases, and phosphorylation has profound effects on the function of this receptor. In this study, we show that ERalpha associates with c-Abl nonreceptor tyrosine kinase. The direct interaction is mediated by two PXXP motifs of ERalpha and the c-Abl SH3 domain. Mutational analysis and in vitro kinase assays show that ERalpha can be phosphorylated on two sites, tyrosine 52 (Y-52) and tyrosine 219 (Y-219). ERalpha phosphorylation by c-Abl stabilizes ERalpha, resulting in enhanced ERalpha transcriptional activity and increased expression of endogenous ERalpha target genes. Furthermore, ERalpha phosphorylation at the Y-219 site affects DNA binding and dimerization by ERalpha. Both the c-Abl inhibitor and the c-Abl kinase dead mutation abolish the c-Abl-induced accumulation of ERalpha and enhancement of ERalpha transcriptional activity, indicating that c-Abl kinase activity is required for regulation of the ERalpha function. Moreover, the ERalpha (Y52,219F) mutant shows reduced breast cancer cell growth and invasion. Taken together, these results show that c-Abl is a novel kinase that upregulates ERalpha expression and promotes breast cancer cell proliferation, suggesting a great potential for this kinase to function as a therapeutic target for breast cancer.

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    • "Of particular note, nilotinib significantly decreased ER levels. It has been demonstrated using transient transfection that Abl regulates ER protein stability via phosphorylation of tyrosine 52 and 219 [58]. Similarly, Abl has been shown to phosphorylate AIB1, a nuclear co-activator for ER, providing further evidence for the role of Abl in modulating ER genomic function [59]. "
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    ABSTRACT: The majority of breast tumors at primary diagnosis are estrogen receptor positive (ER+). Estrogen (E) mediates its effects by binding to the ER. Therapies targeting the estrogenic stimulation of tumor growth reduce mortality from ER+ breast cancer. However, resistance remains a major clinical problem. To identify molecular mechanisms associated with resistance to E-deprivation, we assessed the temporal changes in global gene expression during adaptation to long-term culture of MCF7 human breast cancer cells in the absence of estradiol (E2), long term estrogen deprived (LTED), that leads to recovery of proliferative status and models resistance to an aromatase inhibitor (AI). The expression levels of proteins were determined by western blotting. Proliferation assays were carried out using the dual platelet derived growth factor receptor (PDGFR)/Abelson tyrosine kinase (Abl) inhibitor nilotinib. Luciferase reporter assays were used to determine effects on ER-mediated transactivation. Changes in recruitment of cofactors to the gene regulated by estrogen in breast cancer 1 (GREB1) promoter were determined by chromatin immunoprecipitation (ChIP). Gene expression data were derived from 81 postmenopausal women with ER+ BC pre-treatment and at two-weeks post-treatment with single agent anastrozole in a neoadjuvant trial. The PDGF/Abl canonical pathway was significantly elevated as early as one week post E-deprivation (P = 1.94 E-04) and this became the top adaptive pathway at the point of proliferative recovery (P = 1.15 E-07). Both PDGFRβ and Abl protein levels were elevated in the LTED cells compared to wild type (wt)-MCF7 cells. The PDGF/Abl tyrosine kinase inhibitor nilotinib, suppressed proliferation in LTED cells in the presence or absence of E. Nilotinib also suppressed ER-mediated transcription by destabilizing the ER and reducing recruitment of amplified in breast cancer-1 (AIB1) and the CREB binding protein (CBP) to the promoter of the E-responsive gene GREB1. High PDGFRβ in primary ER+ breast cancer of 81 patients prior to neoadjuvant treatment with an AI was associated with poorer antiproliferative response. Additionally PDGFRβ expression increased after two weeks of AI therapy (1.25 fold, P = 0.003). These preclinical and clinical data indicate that the PDGF/Abl signaling pathway merits clinical evaluation as a therapeutic target with endocrine therapy in ER+ breast cancer.
    Breast cancer research: BCR 05/2012; 14(3):R78. DOI:10.1186/bcr3191 · 5.49 Impact Factor
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    • "This results in enhanced ERα transcriptional activity, both in absence and presence of estradiol. Stabilisation of ERα through c-Abl ultimately leads to proliferation and invasion of breast tumor cells [21]. "
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    ABSTRACT: About two thirds of all human breast cancer cases are estrogen receptor positive. The drug of first choice for these patients is tamoxifen. However, about half of the recurrences after removal of the primary tumor are or become resistant to this drug. While many mechanisms have been identified for tamoxifen resistance in the lab, at present only a few have been translated to the clinic. This paper highlights the role in tamoxifen resistance of phosphorylation by different kinases on different sites of the estrogen receptor. We will discuss the molecular pathways and kinases that are involved in phosphorylation of ERα and how these affect tamoxifen resistance. Finally, we will elaborate on the clinical translation of these observations and the possibility to predict tamoxifen responses in patient tumor samples before treatment onset. The findings made originally on the bench may translate into a better and personalized treatment of breast cancer patients using an old and safe anticancer drug: tamoxifen.
    07/2011; 2011(2):232435. DOI:10.4061/2011/232435
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    ABSTRACT: Multiple sites of phosphorylation on human estrogen receptor α (ERα) have been identified by a variety of methodologies. Now with the emerging availability of phospho-site-specific antibodies to ERα, the relevance of phosphorylation of ERα in human breast cancer in vivo is being explored. Multiple phosphorylated sites in ERα can be detected in multiple breast tumor biopsy samples, providing evidence of their relevance to human breast cancer in vivo. Published data suggest that the detection in primary breast tumors of phosphorylation at some sites in ERα is associated with a better clinical outcome while phosphorylation at other sites is associated with a poorer clinical outcome most often in patients who have been treated with tamoxifen. This suggests the hypothesis that phospho-profiling of ERα in human breast tumors to establish an 'ERα phosphorylation code', may be a more accurate marker of prognosis and/or response to endocrine therapy in human breast cancer.
    Endocrine Related Cancer 02/2011; 18(1):R1-14. DOI:10.1677/ERC-10-0070 · 4.81 Impact Factor
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