A Role for Estrogen Receptor Phosphorylation in the Resistance to Tamoxifen

Leeuw, Renée de; Neefjes, Jacques; Michalides, Rob

doi:10.4061/2011/232435

Cited by 102 publications

(105 citation statements)

References 75 publications

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“…It has been demonstrated that ERa may be phosphorylated on multiple amino acid residues (de Leeuw et al 2011). ERa has an N-terminal domain with a hormone-independent transcriptional activation function (AF-1, amino acids 1-180), a central DNA-binding domain (amino acids 181-263) and a C-terminal ligand-binding domain with a hormone-dependent transcriptional activation function (AF-2; amino acids 302-552).…”

Section: Discussionmentioning

confidence: 99%

“…Because both Ser-118 and Ser-167 are located in the AF-1 region, activation of ERa by phosphorylation of these two sites is ligand-independent. Ser-118 is perhaps the best-studied site of ERa phosphorylation and is widely considered to be a target of ERK, although other kinases such as the glycogen synthase kinse-3 (GSK-3), inhibitor of kappa B kinase (IKK) a, cyclin-dependent kinase 7 (CDK7) and mammalian target of rapamycin (mTOR)/ ribosomal protein S6 kinase (p70S6K) may also phosphorylate this site (de Leeuw et al 2011). Phosphorylation of ERa-Ser118 by ERK increases binding of coactivator SRC-3 (Likhite et al 2006) and renders ERa hypersensitive to E 2 (Vendrell et al 2005).…”

Section: Discussionmentioning

confidence: 99%

“…pERa-Ser118 influences the recruitment of coregulators to ERa-regulated genes pS2, c-myc and cyclin D1 and affects E2-induced gene expression (Duplessis et al 2011). Ser-167 is phosphorylated by Akt, p90 ribosomal S6 kinase (p90RSK) and mTOR/p70S6K (de Leeuw et al 2011). Akt is induced by EGF and IGF (Martin et al 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, in the case of ER, ERK (Kato et al 1995) and Akt (Campbell et al 2001) have been reported to activate the ER pathway by direct phosphorylation of ERa at serine 118 (pERa-Ser118) and serine 167 (pERa-Ser167) respectively in the activation function-1 (AF-1) domain, a region responsible for the transcriptional activity of ER in the absence of ligand. These two sites appear to be the most relevant sites with regard to breast cancer resistance to TAM (de Leeuw et al 2011). Results of studies have indicated a correlation between either pERa-Ser118 or pERa-Ser167 and TAM resistance (Green & Carroll 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Results of previous studies have indicated that phosphorylation of ERa by serine/threonine protein kinases induces TAM resistance (Kato et al 1995, Campbell et al 2001, Park et al 2005, Yamashita et al 2005, Likhite et al 2006, Yamnik et al 2009, Guo et al 2010, de Leeuw et al 2011. Ser-118 and Ser-167 are two of the most reported phosphorylation sites of ERa.…”

Section: Il6 Phosphorylates Era At Ser118 and Ser167 In Ovca Cells Bymentioning

confidence: 99%

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IL6 induces TAM resistance via kinase-specific phosphorylation of ERα in OVCA cells

Wang

Niu

Guo

et al. 2015

Journal of Molecular Endocrinology

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About 40-60% of ovarian cancer (OVCA) cases express ERa, but only a small proportion of patients respond clinically to anti-estrogen treatment with estrogen receptor (ER) antagonist tamoxifen (TAM). The mechanism of TAM resistance in the course of OVCA progression remains unclear. However, IL6 plays a critical role in the development and progression of OVCA. Our recent results indicated that IL6 secreted by OVCA cells may promote the resistance of these cells to TAM via ER isoforms and steroid hormone receptor coactivator-1. Here we demonstrate that both exogenous (a relatively short period of treatment with recombinant IL6) and endogenous IL6 (generated as a result of transfection with a plasmid encoding sense IL6) increases expression of pERa-Ser118 and pERa-Ser167 in non-IL6-expressing A2780 cells, while deleting endogenous IL6 expression in IL6-overexpressing CAOV-3 cells (by transfection with a plasmid encoding antisense IL6) reduces expression of pERa-Ser118 and pERa-Ser167, indicating that IL6-induced TAM resistance may also be associated with increased expression of pERa-Ser118 and pERa-Ser167 in OVCA cells. Results of further investigation indicate that IL6 phosphorylates ERa at Ser118 and Ser167 by triggering activation of MEK/ERK and phosphotidylinositol 3 kinase/Akt signaling, respectively, to activate the ER pathway and thereby induce OVCA cells resistance to TAM. These results indicate that IL6 secreted by OVCA cells may also contribute to the refractoriness of these cells to TAM via the crosstalk between ER and IL6-mediated intracellular signal transduction cascades. Overexpression of IL6 not only plays an important role in OVCA progression but also promotes TAM resistance. Our results indicate that TAM-IL6-targeted adjunctive therapy may lead to a more effective intervention than TAM alone.Key Words

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Il6 Phosphorylates Era At Ser118 and Ser167 In Ovca Cells Bymentioning

confidence: 99%

See 3 more Smart Citations

IL6 induces TAM resistance via kinase-specific phosphorylation of ERα in OVCA cells

Wang

Niu

Guo

et al. 2015

Journal of Molecular Endocrinology

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The proteasome inhibitor Bortezomib (Velcade) as potential inhibitor of estrogen receptor-positive breast cancer

et al. 2015

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Around 70% of breast cancers express the estrogen receptor a (ERa) and depend on estrogen for growth, survival and disease progression. The presence of hormone sensitivity is usually associated with a favorable prognosis. Use of adjuvant antiendocrine therapy has significantly decreased breast cancer mortality in patients with early-stage disease, and anti-endocrine therapy also plays a central role in the treatment of advanced stages. However a subset of hormone receptor-positive breast cancers do not benefit from anti-endocrine therapy, and nearly all hormone receptor-positive metastatic breast cancers ultimately develop resistance to anti-hormonal therapies. Despite new insights into mechanisms of anti-endocrine therapy resistance, e.g., crosstalk between ERa and Her2/neu, the management of advanced hormone-receptor-positive breast cancers that are resistant to anti-endocrine agents remains a significant challenge. In the present study, we demonstrate that the proteasome inhibitor Bortezomib strongly inhibits ERa and HER2/neu expression, increases expression of cyclin-dependent kinase inhibitors, inhibits expression of multiple genes associated with poor prognosis in ERa1 breast cancer patients and induces cell death in ER1 breast cancer cells in both the presence and absence of functional p53. Although Bortezomib increased the levels of p53 and increased the expression of pro-apoptotic target genes in ERa1 breast cancer cells harboring wild-type p53, Bortezomib also exerts anti-tumoral effects on ERa1 breast cancer cells through suppression of ERa expression and inhibition of PI3K/Akt/mammalian target of rapamycin (mTOR) and ERK signaling independently of functional p53. These findings suggest that Bortezomib might have the potential to improve the management of anti-endocrine therapy resistant ERa1 breast cancers independently of their p53 status.

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IGF‐1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER‐positive breast cancer

Kruger

Alexi

Opdam

et al. 2019

Intl Journal of Cancer

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Preclinical studies indicate that activated IGF‐1R can drive endocrine resistance in ER‐positive (ER+) breast cancer, but its clinical relevance is unknown. We studied the effect of IGF‐1R signaling on tamoxifen benefit in patients and we searched for approaches to overcome IGF‐1R‐mediated tamoxifen failure in cell lines. Primary tumor blocks from postmenopausal ER+ breast cancer patients randomized between adjuvant tamoxifen versus nil were recollected. Immunohistochemistry for IGF‐1R, p‐IGF‐1R/InsR, p‐ERα(Ser118), p‐ERα(Ser167) and PI3K/MAPK pathway proteins was performed. Multivariate Cox models were employed to assess tamoxifen efficacy. The association between p‐IGF‐1R/InsR and PI3K/MAPK pathway activation in MCF‐7 and T47D cells was analyzed with Western blots. Cell proliferation experiments were performed under various growth‐stimulating and ‐inhibiting conditions. Patients with ER+, IGF‐1R‐positive breast cancer without p‐IGF‐1R/InsR staining (n = 242) had tamoxifen benefit (HR 0.41, p = 0.0038), while the results for p‐IGF‐1R/InsR‐positive patients (n = 125) were not significant (HR 0.95, p = 0.3). High p‐ERα(Ser118) or p‐ERα(Ser167) expression was associated with less tamoxifen benefit. In MCF‐7 cells, IGF‐1R stimulation increased phosphorylation of PI3K/MAPK proteins and ERα(Ser167) regardless of IGF‐1R overexpression. This could be abrogated by the dual IGF‐1R/InsR inhibitor linsitinib, but not by the IGF‐IR‐selective antibody 1H7. In MCF‐7 and T47D cells, stimulation of the IGF‐1R/InsR pathway resulted in cell proliferation regardless of tamoxifen. Abrogation of cell growth was regained by addition of linsitinib. In conclusion, p‐IGF‐1R/InsR positivity in ER+ breast cancer is associated with reduced benefit from adjuvant tamoxifen in postmenopausal patients. In cell lines, stimulation rather than overexpression of IGF‐1R is driving tamoxifen resistance to be abrogated by linsitinib.

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A Role for Estrogen Receptor Phosphorylation in the Resistance to Tamoxifen

Cited by 102 publications

References 75 publications

IL6 induces TAM resistance via kinase-specific phosphorylation of ERα in OVCA cells

IL6 induces TAM resistance via kinase-specific phosphorylation of ERα in OVCA cells

The proteasome inhibitor Bortezomib (Velcade) as potential inhibitor of estrogen receptor-positive breast cancer

IGF‐1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER‐positive breast cancer

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