Tamoxifen resistance by a conformational arrest of the estrogen receptor α after PKA activation in breast cancer

Michalides, Rob; Griekspoor, Alexander; Balkenende, Astrid; Verwoerd, Desirée; Janssen, Lennert; Jalink, Kees; Floore, Arno; Velds, Arno; Veer, Laura van ‘t; Neefjes, Jacques

doi:10.1016/j.ccr.2004.05.016

Cited by 238 publications

(286 citation statements)

References 37 publications

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“…Importantly, the major phosphorylation site in response to 17bE2 was previously demonstrated to be S118, whereas S167 is only modified in response to MAPK/AKT pathway signaling (Lannigan, 2003). In addition, pS305 was associated with resistance to tamoxifen treatment (Michalides et al, 2004). According to these observations, subcellular fractionation assays showed relatively higher levels of ERa in the cytoplasm of MCF7-LTED cells (Figure 1d).…”

Section: Resultsmentioning

confidence: 60%

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

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Endocrine therapies targeting the proliferative effect of 17b-estradiol through estrogen receptor a (ERa) are the most effective systemic treatment of ERa-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The longterm estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERa. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERa transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)-to pS167-ERa were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERa-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy.

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Section: Resultsmentioning

confidence: 60%

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

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“…In this context, it has been reported that phosphorylation of ERα by EGFR-mediated signaling enhances the estrogeninduced transcriptional activity [49,50]. An increased recruitment of coactivators, such as AIB1 [51], and conformational changes [52] after receptor phosphorylation also contribute to enhanced transcriptional activity of ERα in tamoxifen-resistant breast cancer cells. In addition, an inverse relationship between the expression of ERα and EGFR or c-erbB2 was observed in primary breast cancer samples and was associated with decreased sensitivity to endocrine therapy and a poorer prognosis [47,53].…”

Section: Discussionmentioning

confidence: 99%

E-cadherin mediates the aggregation of breast cancer cells induced by tamoxifen and epidermal growth factor

Mauro

Pellegrino

Lappano

et al. 2009

Breast Cancer Res Treat

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In the present study, we evaluated the ability of 4-hydroxytamoxifen (OHT) and epidermal growth factor (EGF) to regulate homotypic adhesion in MCF7 breast cancer cells. Our results demonstrate that OHT and EGF activate the E-cadherin promoter, increase E-cadherin mRNA and protein expression and enhance homotypic aggregation of MCF7 cells. Interestingly, an ERα and EGFR cross-talk is involved in the E-cadherin expression by OHT and EGF as demonstrated by knocking-down either receptor. On the basis of our findings, the well-established cross-talk between ERα and EGFR could be extended to the modulation of E-cadherin expression by OHT and EGF. Thus, the potential ability of tamoxifen to induce cell-cell aggregation may contribute to the biological response of pharmacological intervention in breast cancer patients.3

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“…PKA phosphorylation at S236 in the DNA-binding domain of the ER promotes dimerization of the ER, and the PKA signaling is shown to promote alteration in the agonist/ antagonist balance of antiestrogens in breast cancer cells (38). Similarly, phosphorylation of S305 in the hinge region of the ERa by PKA is shown to induce resistance to tamoxifen (39). It was also shown that down-regulation of the negative regulator of PKA, PKA-RIa, was associated with tamoxifen resistance before clinical treatment, implicating PKA deregulation in tamoxifen resistance (39) Our study extends these earlier studies that PKA signaling promotes tamoxifen agonistic actions and further suggests that mechanism of PKA action also involve ER coregulator PELP1 phosphorylation as the PELP1 mutation that prevents PKA phosphorylation substantially reduced PKA-mediated tamoxifen actions.…”

Section: Discussionmentioning

confidence: 99%

Growth Factor Regulation of Estrogen Receptor Coregulator PELP1 Functions via Protein Kinase A Pathway

Nagpal

Nair

Chakravarty

et al. 2008

Molecular Cancer Research

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PELP1 (proline-rich, glutamic acid -rich, and leucine-rich protein-1) is a potential proto-oncogene that functions as a coregulator of estrogen receptor (ER), and its expression is deregulated during breast cancer progression. Emerging evidence suggests growth factor signaling crosstalk with ER as one possible mechanism by which breast tumors acquire resistance to therapy. In this study, we examined mechanisms by which growth factors modulate PELP1 functions, leading to activation of ER. Using in vivo labeling assays, we have found that growth factors promote phosphorylation of PELP1. Utilizing a panel of substrate-specific phosphorylated antibodies, we discovered that growth factor stimulation promotes phosphorylation of PELP1 that is recognized by a protein kinase A (PKA) substrate -specific antibody. Accordingly, growth factor -mediated PELP1 phosphorylation was effectively blocked by PKA-specific inhibitor H89. Utilizing purified PKA enzyme and in vitro kinase assays, we obtained evidence of direct PELP1 phosphorylation by PKA. Using deletion and mutational analysis, we identified PELP1 domains that are phosphorylated by PKA. Interestingly, site-directed mutagenesis of the putative PKA site in PELP1 compromised growth factor -induced activation and subnuclear localization of PELP1 and also affected PELP1-mediated transactivation function. Utilizing MCF-7 cells expressing a PELP1 mutant that cannot be phosphorylated by PKA, we provide mechanistic insights by which growth factor signaling regulates ER transactivation in a PELP1-dependent manner. Collectively, these findings suggest that growth factor signals promote phosphorylation of ER coactivator PELP1 via PKA pathway, and such modification may have functional implications in breast tumors with deregulated growth factor signaling. (Mol Cancer Res 2008;6(5):851 -61)

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Tamoxifen resistance by a conformational arrest of the estrogen receptor α after PKA activation in breast cancer

Cited by 238 publications

References 37 publications

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

E-cadherin mediates the aggregation of breast cancer cells induced by tamoxifen and epidermal growth factor

Growth Factor Regulation of Estrogen Receptor Coregulator PELP1 Functions via Protein Kinase A Pathway

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