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1.
Cancer Res ; 61(17): 6360-6, 2001 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-11522626

RESUMEN

Estrogens are direct mitogens for hormone-responsive human breast cancercells, where they promote cell cycle progression and induce transcriptional activation of "immediate early" and cyclin genes. Nongenomic signaling by estrogens, including rapid changes of mitogen-activated protein(MAP) kinase and other signal-transduction-cascades activity, has been proposed to be essential for the mitogenic actions of these hormones and their nuclear receptors. Because regulation of gene transcription is considered a key step in cell cycle control by mitogenic protein kinase cascades, here we investigated the possibility that estrogen might induce the activation of extracellular signal-regulated kinase (Erk) 1/2-, c-Jun NH(2)-terminal kinase-, p38- or protein kinase A-responsive transcription factors in the cell nucleus during stimulation of early G(1) progression, a timing coincident with the maximum effects of these hormones on such enzyme activity. No significant changes in protein kinase-mediated transcription factor activity could be detected here after estrogen stimulation of either MCF-7 or ZR-75.1 cells. Furthermore, these steroids were able to induce activation of the human CCND1 gene promoter, accumulation of cyclin D1 and pRb phosphorylation, all key events in cell cycle stimulation by mitogens, even in the presence of Erk1/2 activation blockade by a MAP kinase-activating kinase (Mek)1/2 inhibitor. Thus, estrogens do not appear to convey significant protein kinase-dependent signaling to the cell nucleus during the early phases of human breast cancer cell stimulation. Furthermore, hormonal regulation of G(1) gene transcription can occur even without additional activation of the Mek-Erk1/2 pathway by estrogen receptors.


Asunto(s)
Neoplasias de la Mama/patología , Estradiol/farmacología , Fase G1/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos , Quinasa 1 de Quinasa de Quinasa MAP , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neoplasias de la Mama/enzimología , Núcleo Celular/enzimología , Núcleo Celular/fisiología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Ciclina D1/biosíntesis , Ciclina D1/genética , Fase G1/fisiología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , MAP Quinasa Quinasa 4 , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína de Retinoblastoma/metabolismo , Células Tumorales Cultivadas , Proteínas Quinasas p38 Activadas por Mitógenos
2.
Breast Cancer Res Treat ; 67(1): 23-33, 2001 May.
Artículo en Inglés | MEDLINE | ID: mdl-11518463

RESUMEN

Overexpression of the cyclin D1 (CCND1) gene, encoding a downstream effector of mitogenic signals that plays a central role in G1 phase progression, is often found in cancerous cells. In sporadic breast cancer (BC), this is one of the most frequent and early genetic lesions identified so far, found in more than 50% of the tumors. Inhibitors of the mevalonate/protein prenylation pathway belong to a new family of cancer therapeutic agents that act by blocking intracellular mitogenic signal transduction pathways, thereby preventing expansion of pre-cancerous foci and inhibiting growth of transformed cells. It is not known at present whether constitutively high intracellular levels of cyclin D1 might interfere with the cytostatic actions of mevalonate/protein prenylation inhibitors. This possibility was investigated here by assessing the cell cycle effects of Simvastatin, a non-toxic upstream inhibitor of the mevalonate pathway, on human BC MCF-7 cells expressing either normal or enhanced levels of cyclin D1 from of a stably transfected, tet-inducible expression vector. Results show that constitutive overexpression of this protein, such as that found in sporadic BCs, does not influence the growth inhibitory effects of Simvastatin in vitro. In addition, D1-overexpressing embryo fibroblasts were also found to be responsive to the cell cycle effects of mevalonate/protein prenylation pathway blockade, further suggesting that high intracellular levels of cyclin D1 do not prevent the cytostatic actions of compounds targeting this metabolic pathway.


Asunto(s)
Neoplasias de la Mama/patología , División Celular/efectos de los fármacos , Ciclina D1/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Proteínas de Neoplasias/metabolismo , Prenilación de Proteína/efectos de los fármacos , Simvastatina/uso terapéutico , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Ciclo Celular/efectos de los fármacos , Humanos , Ácido Mevalónico , Ratas
3.
Mol Cell Endocrinol ; 165(1-2): 199-209, 2000 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-10940498

RESUMEN

Antiestrogens are widely used for breast cancer treatment, where they act primarily by inhibiting the mitogenic action of estrogens on tumor cells. The effects of the pure antiestrogen ICI 182,780 on estrogen-regulated cell cycle phase-specific events were investigated here in synchronously cycling human breast cancer (HBC) cells. In early G(1)-arrested MCF-7 or ZR-75.1 cells, 17beta-estradiol (E2) induces rapid activation of the cyclin/Cdk/pRb pathway, as demonstrated by D-type G(1) cyclins accumulation during the first few hours of hormonal stimulation, followed by sequential accumulation of E, A and B1 cyclins and progressive pRb phosphorylation, as cells progress through the cell cycle. When added to quiescent cells together with E2, ICI 182,780 prevents all of the above hormonal effects. Interestingly, in mid-G(1) cells (2-8 h into estrogen stimulation) the antiestrogen causes rapid reversal of hormone-induced D-type cyclins accumulation and pRb phosphorylation, and still fully inhibits G(1)-S transition rate, while in late-G(1) cells it does not prevent S phase entry but still inhibits significantly DNA synthesis rate, S-phase cyclins accumulation and pRb hyperphosphorylation. These results indicate that pure antiestrogens prevent multiple estrogen-induced cell cycle-regulatory events, each timed to allow efficient G(1) completion, G(1)-S transition, DNA synthesis and cell cycle completion.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Estradiol/análogos & derivados , Moduladores de los Receptores de Estrógeno/farmacología , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias Hormono-Dependientes/patología , Neoplasias de la Mama/metabolismo , Ciclo Celular/efectos de los fármacos , Ciclo Celular/fisiología , División Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/metabolismo , Ciclinas/metabolismo , Estradiol/farmacología , Estrógenos/metabolismo , Femenino , Fulvestrant , Humanos , Neoplasias Hormono-Dependientes/metabolismo , Fosforilación , Proteína de Retinoblastoma/metabolismo , Células Tumorales Cultivadas
4.
Cancer Res ; 58(5): 871-6, 1998 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-9500441

RESUMEN

Cyclin D1 is a target for positive regulation by estrogens in growth-responsive cells, in which it mediates their mitogenic effects. Amplification and overexpression of the cyclin D1 gene (CCND1) might thus represent a genetic lesion inducing hormone-independent growth of transformed cells. Indeed, cyclin D1 overexpression has been found in up to 50% of primary breast cancers, and in about one-third of these cases, this is linked to amplification of the 11q13 chromosomal region, which also includes the CCND1 gene. These tumors are predominantly estrogen receptor-positive, and for this reason, these patients are often selected for adjuvant antiestrogen therapy. No information is available, however, as to whether cyclin D1 overexpression due to gene amplification might interfere with and reduce antiestrogen efficacy. This was investigated here by taking advantage of an experimental model that reproduces cyclin D1 overexpression resulting from increased CCND1 gene dosage in hormone-responsive human breast cancer cells. For this, MCF-7 cells stably transfected with a tet-inducible cyclin D1 expression vector were tested for their in vitro response to steroidal (ICI 182,780) and nonsteroidal (trans-4-hydroxytamoxifen) antiestrogens under condition of low (endogenous only) or high (exogenous) cyclin D1 levels. Results show that although cyclin D1 overexpression seems to interfere with the early cell cycle effects of antiestrogens, it does not prevent their cytostatic actions, so that growth of cyclin-overexpressing MCF-7 cells is still efficiently inhibited in vitro by these drugs.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Cromosomas Humanos Par 11 , Ciclina D1/genética , Antagonistas de Estrógenos/farmacología , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Mama/metabolismo , División Celular/efectos de los fármacos , División Celular/genética , Ciclina D1/biosíntesis , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células Tumorales Cultivadas
5.
Endocrinology ; 138(3): 978-84, 1997 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-9048598

RESUMEN

Cyclin-dependent kinases (cdks) are serine-threonine protein kinases that play a key role in the regulation of the mitotic cycle, in transcription initiation, and in the control of specific metabolic pathways in eukaryotic cells. cdk activity is controlled via phosphode-phosphorylation of the catalytic subunits of these enzymes and their physical association with cyclins and cdk inhibitors. In adult rats, estrogen stimulation results in massive proliferation of endometrial epithelial cells, accompanied by functional and structural modifications in all other tissue components of the uterus. We report here that administration of 17 beta-estradiol (E2) to adult ovariectomized rats induces within the first 25 h significant activation of cdk 4, 5, and 6, but not cdk 2, in the uterus, accompanied by increased expression of D-type (D1-3), A and E cyclin messenger RNAs (mRNAs). Furthermore, expression of the cdk inhibitor p27Kip1, a key regulator of uterine functions, is induced by E2 in this organ. Analysis of RNA extracted from E2-stimulated rat endometria shows early accumulation of D1 and D3, but not D2, cyclin mRNA, preceded by transient accumulation of c-fos mRNA. These results indicate an involvement of cdks and cyclins in estrogen actions in adult rat uterus and suggest that cyclins D1 and D3 are part of the molecular pathway that allows hormonal regulation of G1 progression in endometrial cells.


Asunto(s)
Quinasas Ciclina-Dependientes/metabolismo , Ciclinas/genética , Estradiol/farmacología , Proteínas Proto-Oncogénicas , ARN Mensajero/metabolismo , Útero/metabolismo , Animales , Quinasa 4 Dependiente de la Ciclina , Quinasa 5 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Endometrio/metabolismo , Activación Enzimática , Inhibidores Enzimáticos/metabolismo , Femenino , Ovariectomía , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Tiempo
6.
Biochem Biophys Res Commun ; 220(3): 864-70, 1996 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-8607857

RESUMEN

Inhibitors of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, such as Simvastatin and Lovastatin, reduce the rate of DNA synthesis and proliferation of a wide variety of cell types in vitro, by inducing a cell cycle arrest in G1. In estrogen-free medium, DNA synthesis is reduced by more that 90% following exposure of normal and transformed human breast epithelia] cells to 20 microM Simvastatin or Lovastatin for 24 to 42 hrs. We show here that stimulation of estrogen responsive MCF-7 cells with nanomolar concentrations of 17beta-estradiol (E2) prevents inhibition of DNA synthesis by these compounds. The effect of the hormone is antagonized by both steroidal and non steroidal antiestrogens, and it is not detectable in estrogen receptor-negative MCF-10a cells. Cell cycle analysis demonstrates that HMG-CoA reductase inhibitors are unable to induce G1 arrest of MCF-7 cells in the presence of E2.


Asunto(s)
Ciclo Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Estradiol/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Lovastatina/análogos & derivados , Lovastatina/farmacología , Neoplasias de la Mama , Línea Celular , ADN de Neoplasias/biosíntesis , ADN de Neoplasias/efectos de los fármacos , Factor de Crecimiento Epidérmico/farmacología , Estradiol/análogos & derivados , Congéneres del Estradiol/farmacología , Antagonistas de Estrógenos/farmacología , Femenino , Fulvestrant , Humanos , Cinética , ARN Mensajero/biosíntesis , Simvastatina , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacología , Células Tumorales Cultivadas
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