p38γ Mitogen-activated Protein Kinase (MAPK) Confers Breast Cancer Hormone Sensitivity by Switching Estrogen Receptor (ER) Signaling from Classical to Nonclassical Pathway via Stimulating ER Phosphorylation and c-Jun Transcription

Qi, Xiaomei; Zhi, Huiying; Lepp, Adrienne; Wang, Phillip; Huang, Jian; Basir, Zainab; Chitambar, Christopher R.; Myers, Charles R.; Chen, Guan

doi:10.1074/jbc.m112.349357

Cited by 30 publications

(54 citation statements)

References 55 publications

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“…S2D), pointing further to a critical role of the Ser-459 phosphorylation in the PTPH1 oncogenic activity (18). To demonstrate further the significance of p38␥ phosphorylation of PTPH1, IEC-6/K-Ras cells stably expressed with PTPH1 and p38␥ were incubated with pirfenidone (PFD), a specific p38␥ pharmacological inhibitor (41)(42)(43), and PTPH1 precipitates were analyzed by WB. Results in Fig.…”

Section: Resultsmentioning

confidence: 99%

p38γ Mitogen-activated Protein Kinase Signals through Phosphorylating Its Phosphatase PTPH1 in Regulating Ras Protein Oncogenesis and Stress Response

Hou

Suresh

et al. 2012

Journal of Biological Chemistry

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Background:A cross-talk between a kinase and phosphatase plays a critical role in determining cellular fate. Results: We report that p38␥ phosphorylates its phosphatase PTPH1 in regulation of Ras oncogenesis and stress response. Conclusion:These results indicate that a MAPK can signal through its phosphatase. Significance: These studies reveal a novel mechanism by which a MAPK signals through its phosphatase to determine cellular outcomes.

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Section: Resultsmentioning

confidence: 99%

p38γ Mitogen-activated Protein Kinase Signals through Phosphorylating Its Phosphatase PTPH1 in Regulating Ras Protein Oncogenesis and Stress Response

Hou

Suresh

et al. 2012

Journal of Biological Chemistry

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“…This may be reconsidered if a more specific approach of selective inhibition of P38 MAPK isoforms can be envisaged, as recent preclinical studies have demonstrated the important role played by the P38 MAPK γ isoform in TNBCs in relation with its marked induction of cell cycle arrest in the G(2)/M phase (29) and its effect on the cellular sensitivity to topoisomerase II inhibitors (30). Stimulation of topo IIα gene expression by P38 MAPKγ may contribute to increased topo IIα levels and enhanced antitumor activity of topo II inhibitors (24), therefore opening the field for the investigation of selective inhibitors of the P38 MAPK γ isoform in combination with chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…P38 MAPK isoform γ has been recently shown to be selectively activated by exposure to tamoxifen, consequently recruiting nonclassical ER signaling and increased estrogen cell sensitivity (24). Therefore, increased P38 MAPK activation could define a more malignant, resistant and metastatic breast cancer phenotype and justify the evaluation of P38 MAPK inhibitors in the treatment of invasive and tamoxifenresistant breast carcinomas (14).…”

Section: Introductionmentioning

confidence: 99%

Expression and activation of P38 MAP kinase in invasive ductal breast cancers: Correlation with expression of the estrogen receptor, HER2 and downstream signaling phosphorylated proteins

Merlin¹,

Harlé²,

Lion³

et al. 2013

Oncology Reports

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Abstract. MAP kinase signaling proteins have major implications in the molecular oncogenesis of breast cancers and have been extensively investigated as putative targets for therapy. This study reports the investigation of the expression of P38 MAPK and its phosphorylated form (p-P38 MAPK) in clinical specimens of invasive breast carcinomas and their correlation with estrogen receptor (ER) and HER2 expression, as well as MAPK and PI3 kinase-AKT pathway signaling phosphorylated proteins. Expression levels of P38 MAPK and p-P38 MAPK as well as p-AKT, p-GSK3β, p-S6 kinase, p-MEK1 and p-ERK1/2 were quantitatively assessed using multiplex bead immunoassay in frozen specimens from 45 invasive ductal breast cancers. Twenty-nine specimens were ER + , 15 were HER2 + and 10 were triple-negative breast cancers (TNBCs). P38 MAPK was found to be expressed in all tumor specimens and was significantly (P= 0.002) overexpressed in ER + tumors. P38 MAPK expression was lower in TNBCs than in all of the other tumors.

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“…5), Cdk7 (6), and p38g MAPK (mitogen-activated protein kinase; ref. 7). Increased levels of p-ER/S118 results in enhanced breast cancer sensitivity to TAM (7) and hyperexpressed p-ER/S118 in clinical breast cancer further correlates with a better response to the TAM therapy (8).…”

Section: Introductionmentioning

confidence: 99%

“…7). Increased levels of p-ER/S118 results in enhanced breast cancer sensitivity to TAM (7) and hyperexpressed p-ER/S118 in clinical breast cancer further correlates with a better response to the TAM therapy (8). ER phosphorylation at S305 by PAK1 (p21-activated kinase 1), on the other hand, reduces cellular response to TAM (9), and a cooverexpression of PAK1 with p-ER/S305 in clinical breast cancer is associated with antihormone resistance (10).…”

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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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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p38γ Mitogen-activated Protein Kinase (MAPK) Confers Breast Cancer Hormone Sensitivity by Switching Estrogen Receptor (ER) Signaling from Classical to Nonclassical Pathway via Stimulating ER Phosphorylation and c-Jun Transcription

Cited by 30 publications

References 55 publications

p38γ Mitogen-activated Protein Kinase Signals through Phosphorylating Its Phosphatase PTPH1 in Regulating Ras Protein Oncogenesis and Stress Response

p38γ Mitogen-activated Protein Kinase Signals through Phosphorylating Its Phosphatase PTPH1 in Regulating Ras Protein Oncogenesis and Stress Response

Expression and activation of P38 MAP kinase in invasive ductal breast cancers: Correlation with expression of the estrogen receptor, HER2 and downstream signaling phosphorylated proteins

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

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