ERβ Regulates NSCLC Phenotypes by Controlling Oncogenic RAS Signaling

Nikolos, Fotis; Thomas, Christoforos; Rajapaksa, Gayani; Bado, Igor; Gustafsson, Jan‐Åke

doi:10.1158/1541-7786.mcr-13-0663

Cited by 12 publications

(15 citation statements)

References 49 publications

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“…Thus, it is not inconceivable that the IP-MS detection of WDCP here indicates a true protein-protein interaction rather than unspecific binding. While PPZ0506 has been less used, 14C8 is the most referenced antibody for ERβ in Antibodypedia (http://www.antibodypedia.com/gene/11874/ESR2) and several previous reports find this antibody to work well414243444546. We, however, noted that not only did 14C8 stain tissues that lack ERβ when applied in IHC, it also generated a band of the expected size in WB of negative controls that could easily be mistaken for ERβ.…”

Section: Discussionmentioning

confidence: 81%

Insufficient antibody validation challenges oestrogen receptor beta research

et al. 2017

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The discovery of oestrogen receptor b (ERb/ESR2) was a landmark discovery. Its reported expression and homology with breast cancer pharmacological target ERa (ESR1) raised hopes for improved endocrine therapies. After 20 years of intense research, this has not materialized. We here perform a rigorous validation of 13 anti-ERb antibodies, using well-characterized controls and a panel of validation methods. We conclude that only one antibody, the rarely used monoclonal PPZ0506, specifically targets ERb in immunohistochemistry. Applying this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, we detect ERb protein in testis, ovary, lymphoid cells, granulosa cell tumours, and a subset of malignant melanoma and thyroid cancers. We do not find evidence of expression in normal or cancerous human breast. This expression pattern aligns well with RNA-seq data, but contradicts a multitude of studies. Our study highlights how inadequately validated antibodies can lead an exciting field astray.

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Section: Discussionmentioning

confidence: 81%

Insufficient antibody validation challenges oestrogen receptor beta research

et al. 2017

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“…Similar to other cancers, contradictory effects of ERb have been reported on growth of NSCLC cells (29). We previously observed that upregulation of ERb1 induces cellcycle arrest and apoptosis by inhibiting oncogenic RAS signaling (30). ERb has also been reported to sensitize cancer cells to chemotherapeutic agents.…”

Section: Introductionmentioning

confidence: 89%

“…ERb1 expression constructs were generated by cloning the fulllength ERb1 in the pIRESneo or pLenti6/V5 expression vectors (Clontech Laboratories) as described previously (30,37). H1299 cells were transfected with empty pIRESneo vector or the recombinant pIRESneo-ERb1 plasmid.…”

Section: Cell Transfectionsmentioning

confidence: 99%

ERβ Sensitizes NSCLC to Chemotherapy by Regulating DNA Damage Response

Nikolos

Thomas

Bado

et al. 2018

Molecular Cancer Research

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The expression of wild-type estrogen receptor β (ESR2/ERβ1) correlates with clinical outcome in patients with non-small cell lung cancer (NSCLC). However, the molecular mechanism that accounts for this association is currently poorly understood. ERβ1 was previously linked to chemotherapy response in patients with breast cancer and in breast cancer cells. The effect of the receptor in NSCLC cells after chemotherapy treatment, a common remedy for advanced NSCLC, has not been studied. Here, upregulation of ERβ1 increases the sensitivity of NSCLC cells to treatment with doxorubicin and etoposide. This effect was primarily observed in p53-defecient NSCLC cells. In these cells, ERβ1 either enhanced G-M cell-cycle arrest by activating the checkpoint kinase 1 (Chk1) and altering downstream signaling or induced apoptosis. The expression of p63 target genes that control G-M checkpoint activation was altered by ERβ1 suggesting an ERβ1-p63 transcriptional cooperation in lung cancer cells that affects DNA damage response (DDR). These results suggest involvement of ERβ1 in the mechanism that regulates DNA damage response in NSCLC cells and support the potential predictive and therapeutic value of the receptor in clinical management of the disease. This study demonstrating the impact of ERβ1 on chemosensitivity of NSCLC cells suggests the predictive value of the receptor for successful response of tumors to chemotherapy and the potential benefit of chemotherapy-treated patients from the use of ER ligands. .

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“…However, the expression of cancer-related genes was not altered significantly in the presence of ligands, implying the involvement of other transcription factors in ERβ1 action. 24,31,42,43 In contrast, ligand-dependent effects of ERβ have been observed in cancer cells that express endogenous ERβ1 including MCF-7 cells. 28,44 The expression levels of the receptor, ERα and coregulatory proteins in transfected cells and in cells that express endogenous ERβ1 may be important factors in determining the type of effect (ligand-independent or -dependent) that ERβ1 elicits in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…24,43 In addition to recombinant ERβ1 protein, as a positive control of untagged ERβ1 expression, lysates from H1299 lung cancer cells that had been stably transfected with pIRES-ERβ1 plasmid and validated for ERβ1 expression using different ERβ antibodies were loaded in some of the gels. 43 For the IRE1α-HSP90 co-immunoprecipitations, cells were lysed in a buffer containing 50 mM HEPES, pH 7.4, 150 mM NaCI, 1 mM EDTA, 1 mM ethylene glycol tetraacetic acid, 1% Nonidet P-40, 1% glycerol including protease and phosphatase inhibitors. Lysates were cleared by centrifugation and the supernatants were incubated with anti-HSP90 antibody (MA3-011, ThermoFisher Scientific) overnight at 4°C and A/G agarose beads for 2 h at 4°C.…”

Section: Immunoblotting-immunoprecipitationmentioning

confidence: 99%

ERβ decreases breast cancer cell survival by regulating the IRE1/XBP-1 pathway

et al. 2014

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Unfolded protein response (UPR) is an adaptive reaction that allows cancer cells to survive endoplasmic reticulum (EnR) stress that is often induced in the tumor microenvironment because of inadequate vascularization. Previous studies report an association between activation of the UPR and reduced sensitivity to antiestrogens and chemotherapeutics in estrogen receptor α (ERα)-positive and triple-negative breast cancers, respectively. ERα has been shown to regulate the expression of a key mediator of the EnR stress response, the X-box-binding protein-1 (XBP-1). Although network prediction models have associated ERβ with the EnR stress response, its role as regulator of the UPR has not been experimentally tested. Here, upregulation of wild-type ERβ (ERβ1) or treatment with ERβ agonists enhanced apoptosis in breast cancer cells in the presence of pharmacological inducers of EnR stress. Targeting the BCL-2 to the EnR of the ERβ1-expressing cells prevented the apoptosis induced by EnR stress but not by non-EnR stress apoptotic stimuli indicating that ERβ1 promotes EnR stress-regulated apoptosis. Downregulation of inositol-requiring kinase 1α (IRE1α) and decreased splicing of XBP-1 were associated with the decreased survival of the EnR-stressed ERβ1-expressing cells. ERβ1 was found to repress the IRE1 pathway of the UPR by inducing degradation of IRE1α. These results suggest that the ability of ERβ1 to target the UPR may offer alternative treatment strategies for breast cancer.

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ERβ Regulates NSCLC Phenotypes by Controlling Oncogenic RAS Signaling

Cited by 12 publications

References 49 publications

Insufficient antibody validation challenges oestrogen receptor beta research

Insufficient antibody validation challenges oestrogen receptor beta research

ERβ Sensitizes NSCLC to Chemotherapy by Regulating DNA Damage Response

ERβ decreases breast cancer cell survival by regulating the IRE1/XBP-1 pathway

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