RETRACTED: Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade

Wong, Chi‐Wai; McNally, Christopher J.; Nickbarg, Elliot; Komm, Barry S.; Cheskis, Boris J.

doi:10.1073/pnas.192569699

Cited by 299 publications

(332 citation statements)

References 37 publications

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“…ERa and c-Src bind in a protein complex that has been proposed to involve other proteins such as modulator of nongenomic activity of ER and phosphatidylinositol 3-kinase (16,27,28). Our studies showed hormone-independent interactions between ERa and c-Src that were not altered by estrogen or the K303R-ERa mutation.…”

Section: Discussionmentioning

confidence: 50%

Cooperative action of tamoxifen and c-Src inhibition in preventing the growth of estrogen receptor–positive human breast cancer cells

Herynk

Beyer

Cui

et al. 2006

Molecular Cancer Therapeutics

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It has long been appreciated that estrogenic signaling contributes to breast cancer progression. c-Src is also required for a number of processes involved in tumor progression and metastasis. We have previously identified the K303R mutant estrogen receptor A (ERA) that confers hypersensitivity to low levels of estrogen. Because ERA and c-Src have been shown to interact in a number of different systems, we wanted to evaluate the role of c-Src kinase in estrogen-stimulated growth and survival of ERA-positive breast cancer cells. MCF-7 cells stably expressing the mutant receptor showed increased c-Src kinase activity and c-Src tyrosine phosphorylation when compared with wild-type ERA-expressing cells. A c-Src inhibitor, AZD0530, was used to analyze the biological effects of pharmacologically inhibiting c-Src kinase activity. MCF-7 cells showed an anchoragedependent growth IC 50 of 0.47 Mmol/L, which was increased 4-fold in the presence of estrogen. In contrast, cells stably expressing the mutant ERA had an elevated IC 50 that was only increased 1.4-fold by estrogen stimulation. The c-Src inhibitor effectively inhibited the anchorage-independent growth of both of these cells, and estrogen was able to reverse these effects. When cells were treated with suboptimal concentrations of c-Src inhibitor and tamoxifen, synergistic inhibition was observed, suggesting a cooperative interaction between c-Src and ERA. These data clearly show an important role for ERA and estrogen signaling in c-Src -mediated breast cancer cell growth and survival. Here, we show that c-Src inhibition is blocked by estrogen signaling; thus, the therapeutic use of c-Src inhibitors may require inhibition of ERA in estrogen-dependent breast cancer.

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Section: Discussionmentioning

confidence: 50%

Cooperative action of tamoxifen and c-Src inhibition in preventing the growth of estrogen receptor–positive human breast cancer cells

Herynk

Beyer

Cui

et al. 2006

Molecular Cancer Therapeutics

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“…In recent years, much evidence has shown that in multiple cell types under different experimental conditions, steroid receptors directly interact with several signaling effectors and trigger various biological effects. In addition to Src, these effectors include calmodulin (Castoria et al, 1988), the regulatory subunit of the phosphoinositide 3-kinase, p85a (Simoncini et al, 2000;Castoria et al, 2001), Shc (Song et al, 2002), modulator of non genomic activity of receptor (Wong et al, 2002), protein kinase Cz (Castoria et al, 2004), EGF receptor (Marquez et al, 2001;Migliaccio et al, 2005), and many other signaling or signaling-related proteins. Therefore, approaches similar to those followed in this report, that is, recognition of new receptor/signaling effector interactions and identification of new inhibitors of such interactions, could enable us to specifically inhibit different hormone actions mediated by signal transducing pathways in multiple cell types and in different pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth

et al. 2007

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In human mammary and prostate cancer cells, steroid hormones or epidermal growth factor (EGF) trigger association of the androgen receptor (AR)-estradiol receptor (ER) (a or b) complex with Src. This interaction activates Src and affects the G1 to S cell cycle progression. In this report, we identify the sequence responsible for the AR/Src interaction and describe a 10 amino-acid peptide that inhibits this interaction. Treatment of the human prostate or mammary cancer cells (LNCaP or MCF-7, respectively) with nanomolar concentrations of this peptide inhibits the androgen-or estradiol-induced association between the AR or the ER and Src the Src/Erk pathway activation, cyclin D1 expression and DNA synthesis, without interfering in the receptor-dependent transcriptional activity. Similarly, the peptide prevents the S phase entry of LNCaP and MCF-7 cells treated with EGF as well as mouse embryo fibroblasts stimulated with androgen or EGF. Interestingly, the peptide does not inhibit the S phase entry and cytoskeletal changes induced by EGF or serum treatment of AR-negative prostate cancer cell lines. The peptide is the first example of a specific inhibitor of steroid receptordependent signal transducing activity. The importance of these results is highlighted by the finding that the peptide strongly inhibits the growth of LNCaP xenografts established in nude mice.

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“…Although the mechanisms for hormone therapy resistance remains elusive, recent studies suggest the presence of alternative signaling pathways that activate ER may account for hormonal therapy resistance (19,44,45). Growth factor -mediated phosphorylation of ER and ER coregulatory proteins have been shown to have a role in tamoxifen resistance (15).…”

Section: Discussionmentioning

confidence: 99%

“…PELP1 [proline-rich, glutamic acid -rich, and leucine-rich protein-1; also termed modulator of nongenomic actions of ER (MNAR)] is a recently identified ER coregulator (18,19). PELP1 is a unique coactivator that plays an important role in both the genomic and nongenomic actions of the ER (20).…”

Section: Introductionmentioning

confidence: 99%

“…PELP1 recruits to the ER target gene promoter, interacts with histones and histone-modifying enzymes, and is suggested to play a role in chromatin remodeling activity of the ligandbound ER (21). The ability of PELP1 to interact and couple cytosolic kinases c-Src and phosphatidylinositol-3-kinase to the ER highlights a novel role for PELP1 in nongenomic ER signaling (19,22,23). Recent evidence suggests that PELP1 is a potential proto-oncogene; its expression is deregulated during cancer progression (24).…”

Section: Introductionmentioning

confidence: 99%

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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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RETRACTED: Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade

Cited by 299 publications

References 37 publications

Cooperative action of tamoxifen and c-Src inhibition in preventing the growth of estrogen receptor–positive human breast cancer cells

Cooperative action of tamoxifen and c-Src inhibition in preventing the growth of estrogen receptor–positive human breast cancer cells

Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth

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

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