Tyrosine phosphorylation of estradiol receptor by Src regulates its hormone-dependent nuclear export and cell cycle progression in breast cancer cells

Castoria, Gabriella; Giovannelli, Pia; Lombardi, Maria; Rosa, Claudio De; Giraldi, Tiziana; Falco, Antonietta de; Barone, Maria Vittoria; Abbondanza, Ciro; Migliaccio, Antimo; Auricchio, Ferdinando

doi:10.1038/onc.2011.642

Cited by 62 publications

(67 citation statements)

References 53 publications

(68 reference statements)

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“…Plasmids GFP-ERa and their Y537F mutant were described previously (13). HA-tagged wild-type (WT) PTPH1 and its phosphatase-deficient mutant PTPH1/DA were kindly provided Dr. N.K.…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies further showed that Src-induced ER/Y537 phosphorylation is essential for ER nuclear export (13) and for E6AP-triggered ER degradation (14). Furthermore, increased levels of p-ER/ Y537 expression in clinical breast cancer are associated with a poor therapeutic response to TAM (15) and the Tyr537Asn mutation was detected in metastatic breast cancer (16).…”

Section: Introductionmentioning

confidence: 99%

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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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“…Plasmids GFP-ERa and their Y537F mutant were described previously (13). HA-tagged wild-type (WT) PTPH1 and its phosphatase-deficient mutant PTPH1/DA were kindly provided Dr. N.K.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Recent data suggest that the nuclear export of the estrogen receptor α (ERα) into the cytoplasm is required for estrogendependent activation of DNA synthesis and S-phase entry, resulting in increased proliferative activity of breast cancer cells ( 56,57 ). Following estrogen stimulation, PI3K-AKT phosphorylates FOXO1, also known as forkhead in rhabdomyosarcoma (FKHR; ref.…”

Section: Reviewmentioning

confidence: 99%

“…In addition, estrogen also activates the nonreceptor protooncogene SRC, resulting in tyrosine phosphorylation of ERα, which in turn leads to assembly of an ERα-FKHR complex within the nucleus and its subsequent nuclear export via XPO1. The cytoplasmic localization of the ER-α-FKHR leads to downregulation of FKHR transcriptional activity and upregulation of cyclin D1 transcription, resulting in DNA synthesis and S-phase transition ( 56 ).…”

Section: Reviewmentioning

confidence: 99%

Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy

et al. 2014

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In cancer cells, the nuclear-cytoplasmic transport machinery is frequently disrupted, resulting in mislocalization and loss of function for many key regulatory proteins. In this review, the mechanisms by which tumor cells co-opt the nuclear transport machinery to facilitate carcinogenesis, cell survival, drug resistance, and tumor progression will be elucidated, with a particular focus on the role of the nuclear-cytoplasmic export protein. The recent development of a new generation of selective inhibitors of nuclear export (XPO1 antagonists) and how these novel anticancer drugs may bring us closer to the implementation of this therapeutic strategy in the clinic will be discussed. Signifi cance:The nuclear transport mechanism is dysregulated in many malignancies and is associated with dysfunction of many regulatory proteins. Targeting this mechanism as an anticancer strategy has been compelling, and novel agents that selectively inhibit the nuclear export pathway have demonstrated preliminary evidence of clinical effi cacy with an acceptable safety profi le. Cancer Discov; 4(5); 527-37.

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“…Abnormal protein tyrosine phosphorylation underlies various diseases of deregulated growth and differentiation, including cancer [9][10][11]. Src-homology 2 domain-containing phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the first identified proto-oncogene PTPN11.…”

Section: Introductionmentioning

confidence: 99%

The Tyrosine Phosphatase SHP2: A Key Molecule Linked both Type 2 Diabetes and Cancers?

Luo¹,

Tang²,

Yang³

et al. 2014

Med chem

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Emerging epidemiological evidence suggests that T2DM may be associated with an increased risk of certain cancers. However, the underlying molecular mechanism linked these two diseases remains largely unknown. SHP2, a non-receptor protein tyrosine phosphatase encoded by pro-oncogene PTPN11, has been reported involved in insulin resistance through PI3K/Akt/mOTR signaling and has also been considered to play a vital role in carcinogenesis via Ras/Erk pathways. Based on our previous studies, we hypothesize that SHP2 may present a key molecule linked both T2DM and cancers through both Ras/Erk and PI3K/AKT/mTOR signaling pathways. We believe that the comprehensive and detailed investigation of SHP2 may provide a new insight into the underlying molecular mechanism linked both T2DM and cancers, thereby facilitating the process to discover novel therapeutic targets to prevent and treat cancers.

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Tyrosine phosphorylation of estradiol receptor by Src regulates its hormone-dependent nuclear export and cell cycle progression in breast cancer cells

Cited by 62 publications

References 53 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

Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy

The Tyrosine Phosphatase SHP2: A Key Molecule Linked both Type 2 Diabetes and Cancers?

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