Effects of 12-O-Tetradecanoylphorbol-13-acetate on Estrogen Receptor Activity in MCF-7 Cells

Martin, Mary Beth; García-Morales, Pilar; Stoica, Adriana; Solomon, Harrison B.; Pierce, Meredith; Katz, Deborah; Zhang, Shimin; Danielsen, Mark; Saceda, Miguel

doi:10.1074/jbc.270.42.25244

Cited by 40 publications

(21 citation statements)

References 41 publications

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“…A first hint on the interaction between PKCd and ERa came from the downregulation of both proteins observed after treatment of ERa-positive breast cancer cells with TPA and estradiol, which was in line with reports on the downregulation of PKCd by TPA and estrogen (Gschwendt, 1999;Shanmugam et al, 1999). Other authors reported that long-term treatment of MCF-7 cells with TPA resulted in a block of ERa activity (Martin et al, 1995) or a decrease of ERa protein, ERa mRNA and DNA binding capacity (Saceda et al, 1991). These findings suggested a crosstalk between PKCd and ERa functions, and we hypothesized that PKCd signalling may be related to ERa activation.…”

Section: Discussionsupporting

confidence: 75%

Impact of PKCδ on estrogen receptor localization and activity in breast cancer cells

et al. 2005

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Regulation of estrogen receptor (ER) function in breast cancer cells is a complex process involving different signalling mechanisms. One signal transduction component that appears to influence ER signalling is protein kinase C (PKC). PKCd is a particular isoenzyme of the novel PKC subfamily that plays a role in growth control, differentiation and apoptosis. The aim of the present study was to investigate the impact of PKCd on the regulation of the transcriptional activity of the human ERa. By using 12-O-tetradecanoylphorbol-13-acetate (TPA), Bryostatin1 and Rottlerin, we show that active PKCd is a proproliferative factor in estrogen-dependent breast cancer cells. Furthermore, activation of PKCd by TPA resulted in activation and nuclear translocation of ERa and in an increase of ER-dependent reporter gene expression. Transfection and expression of the regulatory domain RDd of PKCd, which is inhibitory to PKCd, inhibited the TPA-induced ERa activation and translocation. ERa was not phosphorylated by PKCd; however, glycogen synthase kinase-3 (GSK3) was identified as a substrate of PKCd. The expression of RDd resulted in a decrease of TPA-induced GSK3 phosphorylation and translocation into the nucleus. We suggest that GSK3 plays a role in the PKCd-related nuclear translocation of ERa.

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Section: Discussionsupporting

confidence: 75%

Impact of PKCδ on estrogen receptor localization and activity in breast cancer cells

et al. 2005

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“…4A-D). The effect of TPA on estrogen receptor gene activation is cell and promoter specific, and probably requires the synthesis or activation of a factor(s) following stimulation (Cho & Katzenellenbogen 1993, Martin et al 1995.…”

Section: Discussionmentioning

confidence: 99%

Modulation of mouse estrogen receptor transcription activity by protein kinase C delta

Lahooti

Thorsen²,

Aakvaag³

1998

Journal of Molecular Endocrinology

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The effect of protein kinase C (PKC) on the transcriptional activity of the mouse estrogen receptor was investigated. The receptor was expressed transiently in Cos-1 and NIH3T3 cells in the presence of wild-type, dominant negative or constitutively active forms of PKC . Transfection experiments demonstrated that PKC stimulated both unliganded and liganded estrogen receptor transcriptional activity. This stimulatory effect was not observed using PKC or PKC . 4-Hydroxytamoxifen and the pure anti-estrogen ICI 164,384 reduced receptor transcriptional activity in the presence of PKC . The stimulatory effect of PKC on estrogen receptor transcriptional activity was mediated by the N-terminal activation function 1 (AF-1) domain. The reduced stimulatory effect of PKC on transcriptional activity of the phosphorylation defective mutant of estrogen receptor suggests that phosphorylation of serine 122 in the AF-1 region may mediate the modulatory effect of PKC . Wild-type PKC caused a twofold increase in estrogen receptor phosphorylation, while a dominant negative mutant of PKC reduced the receptor phosphorylation to five percent of that caused by wild-type PKC . Our results suggest that PKC participates in the signaling pathways that lead to estrogen receptor phosphorylation and its effect on estrogen receptor transcriptional activation is both cell type and promoter specific.

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“…Evidence suggests that activation of growth factor signaling might indeed reduce ERa expression and/or function. For example, treatment with EGF, IGF-I, TGFb or phorbol myristate acetate (TPA) reduces the levels of ERa mRNA and protein in MCF-7 cells (Martin et al 1995, Stoica et al 1997, 2000a. Increased signaling through EGFR, PI3K/AKT, PKA and PKC is involved in this phenomenon.…”

Section: Growth Factor Signaling In Resistance To Endocrine Therapymentioning

confidence: 99%

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

Normanno

Maïo

Maio

et al. 2005

Endocr Relat Cancer

257

224

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Tamoxifen has been the mainstay of hormonal therapy in both early and advanced breast cancer patients for approximately three decades. The availability of novel compounds such as aromatase inhibitors (AIs) and fulvestrant, with different mechanism of action, is changing the scenario of endocrine treatment of postmenopausal breast cancer patients. In this review article, we have summarized the current knowledge of the mechanisms of resistance to endocrine therapy, in order to derive information that might be useful for therapeutic intervention. We propose that resistance to endocrine therapy is a progressive, step-wise phenomenon induced by the selective pressure of hormonal agents, which leads breast cancer cells from an estrogen-dependent, responsive to endocrine manipulation phenotype to a non-responsive phenotype, and eventually to an estrogenindependent phenotype. In particular, evidence suggests for each 'action' introduced to block estrogen stimulation of breast cancer cells (i.e. treatment with anti-estrogen), there are one or more corresponding 'reactions' that tumor cells can use to escape our attempts to block their growth: estrogen hypersensitivity associated with increased transcriptional activity of estrogen receptor a (ERa) and/or increased non-genomic activity of ERa, estrogen supersensitivity, increased growth factor signaling, suppression of ERa expression and finally estrogen independence. Activation of growth factor signaling is involved in each step of this phenomenon, and might ultimately substitute estrogen in sustaining the growth and the survival of breast cancer cells. In this respect, results of pre-clinical and clinical studies with AIs, fulvestrant and signaling inhibitors sustain this hypothesis. More importantly, the knowledge of the mechanisms involved in the resistance of breast cancer cells to endocrine therapy offers potential for novel therapeutic strategies.

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Effects of 12-O-Tetradecanoylphorbol-13-acetate on Estrogen Receptor Activity in MCF-7 Cells

Cited by 40 publications

References 41 publications

Impact of PKCδ on estrogen receptor localization and activity in breast cancer cells

Impact of PKCδ on estrogen receptor localization and activity in breast cancer cells

Modulation of mouse estrogen receptor transcription activity by protein kinase C delta

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

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