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

He, Xiaoqing; Zheng, Zhu-Jun; Song, Ting; Wei, Congwen; Ma, Helen; Ma, Qingjun; Zhang, Y; Xu, Yang; Shi, Wei; Ye, Q; Zhong, Hui

doi:10.1038/onc.2009.513

Cited by 50 publications

(38 citation statements)

References 62 publications

(65 reference statements)

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“…However, we cannot rule out whether Y537-independent mechanisms may also be involved in the PTPH1-induced sensitization. One recent study reported that ER is also phosphorylated at Y52 and/or Y219 by c-Abl, which is involved in breast cancer invasion and growth (34). Moreover, studies with a 6-amino acid peptide that mimics the sequence around the phosphotyrosine residue 537 showed that it disrupted the Src-ER interaction and blocked breast cancer growth in vitro and in mice (35).…”

Section: Discussionmentioning

confidence: 99%

Protein-Tyrosine Phosphatase H1 Increases Breast Cancer Sensitivity to Antiestrogens by Dephosphorylating Estrogen Receptor at Tyr537

Suresh

Migliaccio

et al. 2014

Molecular Cancer Therapeutics

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Estrogen receptor a (ERa or ER) is the only target of breast cancer therapy using antiestrogens. However, about 50% of ER-expressing breast cancer is intrinsically refractory to the antihormone therapy and strategies to improve the therapeutic response are urgently needed. Dynamic ER phosphorylation and dephosphorylation play an important role in ER activity and antihormone response. Although more than 10 kinases participate in phosphorylating ER protein, phosphatases involved remain mostly unidentified. Here, we tested the hypothesis that the protein-tyrosine phosphatase H1 (PTPH1) may regulate ER tyrosine phosphorylation and thereby impact breast cancer antihormone sensitivity. Our results showed that PTPH1 dephosphorylates ER at Tyr537 in vitro and in breast cancer cells. Moreover, PTPH1 stimulates ER nuclear accumulation and increases breast cancer sensitivity to tamoxifen (TAM) and/or fulvestrant in cell culture and in a xenograft model. Further analysis revealed that PTPH1 depends on its catalytic activity to stimulate ER nuclear accumulation and to enhance breast cancer antihormone sensitivity. These studies thus identified PTPH1 as a novel ER phosphatase and further demonstrate a therapeutic potential of enhancing breast cancer sensitivity to antiestrogens through dephosphorylating ER by PTPH1. Mol Cancer Ther; 13(1); 230-8. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Protein-Tyrosine Phosphatase H1 Increases Breast Cancer Sensitivity to Antiestrogens by Dephosphorylating Estrogen Receptor at Tyr537

Suresh

Migliaccio

et al. 2014

Molecular Cancer Therapeutics

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“…The reporter constructs ERE-Luc, catD-Luc, and pS2-Luc and the expression vectors for ERα, Flag-tagged ERα, and HA-tagged ERα have been described previously (46). Other mammalian expression vectors encoding Flag-, Myc-, or HA-fusion proteins tagged at the amino terminus were constructed by inserting PCR-amplified fragments into pcDNA3 (Invitrogen) or pIRESpuro2 (Clontech).…”

Section: Methodsmentioning

confidence: 99%

“…Cell extracts were prepared, immunoprecipitated, and analyzed as previously described (46). An aliquot of the total lysate [5% (vol/vol)] was included as a control for the interaction assay.…”

Section: Methodsmentioning

confidence: 99%

Elevated expression of TANK-binding kinase 1 enhances tamoxifen resistance in breast cancer

Wei¹,

Cao

Yang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Resistance to antiestrogens is one of the major challenges in breast cancer treatment. Although phosphorylation of estrogen receptor α (ERα) is an important factor in endocrine resistance, the contributions of specific kinases in endocrine resistance are still not fully understood. Here, we report that an important innate immune response kinase, the IκB kinase-related TANK-binding kinase 1 (TBK1), is a crucial determinant of resistance to tamoxifen therapies. We show that TBK1 increases ERα transcriptional activity through phosphorylation modification of ERα at the Ser-305 site. Ectopic TBK1 expression impairs the responsiveness of breast cancer cells to tamoxifen. By studying the specimens from patients with breast cancer, we find a strong positive correlation of TBK1 with ERα, ERα Ser-305, and cyclin D1. Notably, patients with tumors highly expressing TBK1 respond poorly to tamoxifen treatment and show high potential for relapse. Therefore, our findings suggest that TBK1 contributes to tamoxifen resistance in breast cancer via phosphorylation modification of ERα.T ANK-binding kinase 1 (TBK1) and IκB kinase e (IKKe) are two IKK-related serine/threonine kinases that display 64% sequence identity and trigger the antiviral response of interferons (IFN) through NF-κB activation and interferon regulatory transcription factor (IRF) 3/7 phosphorylation (1-3). In addition to the proposed roles of IKK-related kinases in controlling transcription factors NF-κB and IRF, the involvement of TBK1 and IKKe in AKT-induced oncogenic transformation has been demonstrated in a recent study (4). TBK1 is identified as a Raslike (Ral) B effector in the Ral guanine nucleotide exchange factor pathway that is required for Ras-induced transformation (5). IKKe acts downstream of the PI3K-AKT pathway and cooperates with activated MEK to promote cellular transformation (6). IKKe has also been identified recently as a breast cancer oncogene that is frequently amplified or overexpressed in human breast cancer, and the phosphorylation of ERα by IKKe contributes to tamoxifen resistance in breast cancer (7-9). Interestingly, TBK1 is also highly expressed in breast cancer (10), and knocking down TBK1 diminishes the viability of MCF-7 cells (9). However, the exact role of TBK1 in breast cancer remains unclear.Estrogen receptor α (ERα) is a nuclear receptor that exerts a profound influence on the initiation and progression of breast cancer by regulating cell transformation, proliferation, and metastasis (11-13). For ERα-positive patients with breast cancer, targeting the ER signaling pathway with tamoxifen, a selective ER modulator, is efficacious in both prevention and treatment of breast cancer (14). Unfortunately, a substantial proportion of patients are intrinsically resistant to this therapy, and a significant number of patients with advanced disease eventually develop acquired resistance to the treatment (15-18). ERα is a key determinant of breast cancer susceptibility to endocrine therapy. Recent studies demonstrate that ERα phosphorylation ...

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“…The estrogen-responsive reporter construct ERE-Luc and eukaryotic expression vectors for FLAG-tagged ERα and ERβ have been described previously (57)(58)(59). Other mammalian expression vectors encoding FLAG-, MYC-, or HA-fusion proteins tagged at the amino terminus were constructed by inserting PCR-amplified fragments into pcDNA3 (Invitrogen) or pIRESpuro2 (Clontech).…”

Section: Methodsmentioning

confidence: 99%

PES1 promotes breast cancer by differentially regulating ERα and ERβ

Cheng¹,

Li²,

Han³

et al. 2012

J. Clin. Invest.

101

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The initiation of breast cancer is associated with increased expression of tumor-promoting estrogen receptor α (ERα) protein and decreased expression of tumor-suppressive ERβ protein. However, the mechanism underlying this process is unknown. Here we show that PES1 (also known as Pescadillo), an estrogen-inducible protein that is overexpressed in breast cancer, can regulate the balance between ERα and ERβ. We found that PES1 modulated many estrogen-responsive genes by enhancing the transcriptional activity of ERα while inhibiting transcriptional activity of ERβ. Consistent with this regulation of ERα and ERβ transcriptional activity, PES1 increased the stability of the ERα protein and decreased that of ERβ through the ubiquitin-proteasome pathway, mediated by the carboxyl terminus of Hsc70-interacting protein (CHIP). Moreover, PES1 transformed normal human mammary epithelial cells and was required for estrogen-induced breast tumor growth in nude mice. Further analysis of clinical samples showed that expression of PES1 correlated positively with ERα expression and negatively with ERβ expression and predicted good clinical outcome in breast cancer. Our data demonstrate that PES1 contributes to breast tumor growth through regulating the balance between ERα and ERβ and may be a better target for the development of drugs that selectively regulate ERα and ERβ activities. IntroductionThe association between estrogen and breast cancer was recognized over 100 years ago. Estrogen exerts its function through its 2 nuclear receptors, estrogen receptor α (ERα) and ERβ (1, 2). ER belongs to a superfamily of ligand-activated transcription factors that share structural similarity characterized by several functional domains. N-terminal estrogen-independent and C-terminal estrogen-dependent activation function domains (AF1 and AF2, respectively) contribute to the transcriptional activity of the 2 receptors. The DNAbinding domain of the ERs is centrally located. The ligand-binding domain, overlapping AF2, shows 58% homology between ERα and ERβ. The DNA-binding domain is identical between the 2 receptors, except for 3 amino acids. However, the AF1 domain of ERβ has only 28% homology with that of ERα. The binding of estrogen to ER leads to ER dimerization and its recruitment to the estrogenresponsive elements (EREs) on the promoters of ER target genes, thereby either enhancing or repressing gene activation.The development of breast cancer is associated with dysregulation of ER expression (3-8). Compared with that in normal breast tissues, the proportion of cells expressing ERα is increased, whereas ERβ expression is reduced, in hormone-dependent breast tumors. The ratio of ERα/ERβ expression is higher in breast tumors than in normal tissues, and ERα and ERβ are antagonistic to each other. ERα mediates the tumor-promoting effects of estrogens, whereas ERβ inhibits breast cancer cell growth. ERβ reduces cell proliferation induced by ERα activation. Although ERα and ERβ have been shown to have a yin-yang relationship in breast tumorige...

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

Cited by 50 publications

References 62 publications

Protein-Tyrosine Phosphatase H1 Increases Breast Cancer Sensitivity to Antiestrogens by Dephosphorylating Estrogen Receptor at Tyr537

Protein-Tyrosine Phosphatase H1 Increases Breast Cancer Sensitivity to Antiestrogens by Dephosphorylating Estrogen Receptor at Tyr537

Elevated expression of TANK-binding kinase 1 enhances tamoxifen resistance in breast cancer

PES1 promotes breast cancer by differentially regulating ERα and ERβ

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