Estrogen Receptor Inhibits c-Jun-dependent Stress-induced Cell Death by Binding and Modifying c-Jun Activity in Human Breast Cancer Cells

Qi, Xiaomei; Borowicz, Stanley; Pramanik, Rocky; Schultz, Richard M.; Han, Jiahuai; Chen, Guan

doi:10.1074/jbc.m311492200

Cited by 29 publications

(47 citation statements)

References 55 publications

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“…In fact, the roles of c-Jun in human cancer remained controversial. Conflict reports have indicated it may function as a proapoptotic (Cuadrado et al, 2004;Qi et al, 2004) or antiapoptotic mediators (Johnsto et al, 1999;Huang et al, 2004) determined upon cellular context. However, our finding of decreased c-Jun phosphorylation in both breast cancer cell lines hence suggested that c-Jun was unlikely an antiapoptotic or proto-oncogene in those two breast cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…c-Jun, a major component of the AP-1 transcription factor, was reported to be either proapoptotic (Cuadrado et al, 2004;Qi et al, 2004) or antiapoptotic (Johnsto et al, 1999;Huang et al, 2004) depending upon cellular contexts. One example of cellular regulators involved in the phosphorylation of c-Jun in breast cancer was demonstrated to be the mitogenactivated protein kinase phosphatases (Wang et al, 2003).…”

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confidence: 99%

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Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

et al. 2005

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Activation of kinases signalling pathways contributes to various malignant phenotypes in human cancers, including breast tumour. To examine the possible activation of these signalling molecules, we examined the phosphorylation status in 12 protein kinases and transcription factors in normal primary human mammary epithelial cells, telomerase-immortalised human breast epithelial cell line, and two breast cancer lines, MDA-MB-468 and MCF-7, using Kinexus phosphorylated protein screening assays. The phosphorylation of FAK, mTOR, p70S6K, and PDK-1 were elevated in both breast cancer cell lines, whereas the phosphorylation of AKT, EGFR, ErbB2/ Her2, PDGFR, Shc, and Stat3 were elevated in only one breast cancer line compared to normal primary mammary epithelial cells and telomerase-immortalised breast epithelial cells. The same findings were confirmed by Western blotting and by kinase assays. We further substantiated the phosphorylation status of these molecules in tissue microarray slides containing 89 invasive breast cancer tissues as well as six normal mammary tissues with immunohistochemistry staining using phospho-specific antibodies. Consistent findings were obtained as greater than 70% of invasive breast carcinomas expressed moderate to high levels of phosphorylated PDK-1, AKT, p70S6K, and EGFR. In sharp contrast, phosphorylation of the same proteins was nearly undetectable or was at low levels in normal mammary tissues under the same assay. Elevated phosphorylation of PDK-1, AKT, mTOR, p70S6K, S6, EGFR, and Stat3 were highly associated with invasive breast tumours (Po0.05). Taken together, our results suggest that activation of these kinase pathways by phosphorylation may in part account for molecular pathogenesis of human breast carcinoma. Particularly, moderate to high level of PDK-1 phosphorylation was found in 86% of high-grade metastasised breast tumours. This is the first report demonstrating phosphorylation of PDK-1 is frequently elevated in breast cancer with concomitantly increased phosphorylation of downstream kinases, including AKT, mTOR, p70S6K, S6, and Stat3. This finding thus suggested PDK-1 may promote oncogenesis in part through the activation of AKT and p70S6K and rationalised that PDK-1 as well as downstream components of PDK-1 signalling pathway may be promising therapeutic targets to treat breast cancer. Breast cancer remains to be a major cause of death in women worldwide, despite improvements in cancer prevention, early detection, treatment, and understanding the molecular pathogenesis. It hence demands an urgent need to unveil the exact mechanism of oncogenesis and tumour progression, which may prelude the development of new strategies for treatment. Breast carcinoma emerges through multistep processes progressing from hyperplasia to premalignant change, in situ carcinoma, invasion, and distal metastasis, in concomitant with gain of oncogenic activities and loss of tumour suppressor gene functions.Protein kinases have been implicated in playing crucial roles in regulating cell growth, met...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

et al. 2005

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“…Qi and co-workers [30] found some hints on binding of ERa and c-jun as a suppressor of stress-induced cell death. Another group detected an in vitro binding of immobilized c-jun to recombinant ERa, simultaneously negating an interaction of ERa and c-fos [31].…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor α attenuates transforming growth factor-β signaling in breast cancer cells independent from agonistic and antagonistic ligands

Stope

Popp²,

Knabbe³

et al. 2009

Breast Cancer Res Treat

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To investigate a presumed crosstalk between estrogen receptor a (ERa) and the TGF-b signaling pathway in breast cancer, we analyzed the TGF-b-induced expression of the plasminogen activator inhibitor 1 (PAI-1) gene in ER-positive MCF-7 cells. After siRNA-mediated knock-down of endogenous ERa, the transcription level of PAI-1 was upregulated, pointing to an attenuation of TGF-b signaling by the presence of ERa. We verified these findings by a vice versa approach using a primary ER-negative cell model transiently overexpressing either ERa or ERb. We found that ERa, but not ERb, led to a strong inhibition of the TGF-b1 signal, monitored by TGF-b reporter assays. This attenuation was completely independent of receptor stimulation by b-estradiol (E2) or inhibition by the pure antagonist ICI 182.780 (ICI). Our results indicate a permanent repression of PAI-1 by ERa and suggest a ligand-independent crosstalk between ERa and TGF-b signaling in breast cancer cells.

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“…Transfection, Viral Infection, and Colony Formation-The constructs for expressing p38␥ and its nonphosphorable mutant p38␥/AGF (by changing TGY to AGF) were provided by Dr. J. Han (34). The V5-tagged pcDNA3 vector (Invitrogen) was used to transiently express ER and its mutants (35). The vectors expressing the fusion protein constructs including the constitutively active (CA) p38␥ (MKK6-p38␥), its nonphosphorable dominant negative mutant (MKK6-p38␥/AGF), and their p38␣ counterparts were described previously (24).…”

Section: Methodsmentioning

confidence: 99%

“…The vectors expressing the fusion protein constructs including the constitutively active (CA) p38␥ (MKK6-p38␥), its nonphosphorable dominant negative mutant (MKK6-p38␥/AGF), and their p38␣ counterparts were described previously (24). The tetracycline-inducible system (Tet-on; Invitrogen) was used to express the MKK6-p38 fusion protein in MCF-7 cells and to express ER and ER/S118A in 231 cells, as described previously (23,29,35). To deplete p38␥ expression, lentiviral vectors expressing shp38␥ or the control shLuc were transfected into packaging cells, and supernatants were collected for infecting target cells, followed by an antibiotic selection (25).…”

Section: Methodsmentioning

confidence: 99%

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

Zhi

Lepp

et al. 2012

Journal of Biological Chemistry

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Estrogen Receptor Inhibits c-Jun-dependent Stress-induced Cell Death by Binding and Modifying c-Jun Activity in Human Breast Cancer Cells

Cited by 29 publications

References 55 publications

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

Estrogen receptor α attenuates transforming growth factor-β signaling in breast cancer cells independent from agonistic and antagonistic ligands

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

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