RESUMEN

OBJECTIVE: The Portable Warrior Test of Tactical Agility (POWAR-TOTAL) is a performance-based test designed to assess active-duty service members diagnosed with mild traumatic brain injuries (mTBIs) and could potentially inform return to duty decisions. To examine the validity and responsiveness of the POWAR-TOTAL measure, this study collected self-reported and performance measures by active-duty service members before and after an episode of physical therapist care. METHODS: Seventy-four individuals, enrolled in care for mTBI symptoms at 1 of 2 concussion specialty Intrepid Spirit Centers, were examined the week that they initiated physical therapy with the intention to return to active duty. Self-reported measures of concussion symptoms, pain, posttraumatic stress, headache, dizziness, and sleep quality were used, as were concurrent measures of mobility and balance. The POWAR-TOTAL task (motor and cognitive skills in single and dual-task conditions) was administered. Forty-nine active-duty service members returned for posttherapy testing using the same test battery. Effect sizes for change in measures were calculated. Construct validity was assessed by correlating change scores on POWAR with concurrent self-report and mobility measures. Responsiveness was evaluated using an anchor-based approach. RESULTS: Significant improvements in self-reported and performance-based measures, including POWAR, were observed after therapy with moderate to large effect sizes. Improvement in POWAR performance correlated with improvement in both performance and self-reported measures. After therapy, individuals who registered improvement on the Patient Global Impression of Change scale demonstrated significantly faster POWAR motor performance than those who rated little or no improvement in their condition. CONCLUSION: The POWAR-TOTAL captured improvement on a military-specific task after completing physical therapy for mTBI and could serve as an indicator of physical recovery and readiness for return to duty. IMPACT: Challenging cognitive and motor measures for service members may aid in the assessment of recovery and the ability to successfully return to duty after concussion as part of a comprehensive examination approach.

Asunto(s)

Conmoción Encefálica , Personal Militar , Humanos , Conmoción Encefálica/rehabilitación , Reinserción al Trabajo , Pruebas Neuropsicológicas , Modalidades de Fisioterapia , Autoinforme , Personal Militar/psicología

RESUMEN

Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins. IRS-null breast cancer cells (T47D-YA) were engineered to express IRS-1 or IRS-2 alone and their ability to mediate IGF ligand-induced proliferation, motility, and gene expression determined. Global gene expression signatures reflecting IRS adaptor specific and primary vs. secondary ligand response were derived (Early IRS-1, Late IRS-1, Early IRS-2 and Late IRS-2) and functional pathway analysis examined. IRS isoforms mediated distinct gene expression profiles, functional pathways, and breast cancer subtype association. For example, IRS-1/2-induced TGFb2 expression and blockade of TGFb2 abrogated IGF-induced cell migration. In addition, the prognostic value of IRS proteins was significant in the luminal B breast tumor subtype. Univariate and multivariate analyses confirmed that IRS adaptor signatures correlated with poor outcome as measured by recurrence-free and overall survival. Thus, IRS adaptor protein expression is required for IGF ligand responses in breast cancer cells. IRS-specific gene signatures represent accurate surrogates of IGF activity and could predict response to anti-IGF therapy in breast cancer.

Asunto(s)

Neoplasias de la Mama/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas Sustrato del Receptor de Insulina/biosíntesis , Proteínas de Neoplasias/biosíntesis , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Humanos , Pronóstico , Factor de Crecimiento Transformador beta2/biosíntesis

RESUMEN

BACKGROUND: Control of mRNA translation is fundamentally altered in cancer. Insulin-like growth factor-I (IGF-I) signaling regulates key translation mediators to modulate protein synthesis (e.g. eIF4E, 4E-BP1, mTOR, and S6K1). Importantly the Amplified in Breast Cancer (AIB1) oncogene regulates transcription and is also a downstream mediator of IGF-I signaling. MATERIALS AND METHODS: To determine if AIB1 also affects mRNA translation, we conducted gain and loss of AIB1 function experiments in estrogen receptor alpha (ERα)(+) (MCF-7L) and ERα(-) (MDA-MB-231, MDA-MB-435 and LCC6) breast cancer cells. RESULTS: AIB1 positively regulated IGF-I-induced mRNA translation in both ERα(+) and ERα(-) cells. Formation of the eIF4E-4E-BP1 translational complex was altered in the AIB1 ERα(+) and ERα(-) knockdown cells, leading to a reduction in the eIF4E/4E-BP1 and eIF4G/4E-BP1 ratios. In basal and IGF-I stimulated MCF-7 and LCC6 cells, knockdown of AIB1 decreased the integrity of the cap-binding complex, reduced global IGF-I stimulated polyribosomal mRNA recruitment with a concomitant decrease in ten of the thirteen genes tested in polysome-bound mRNAs mapping to proliferation, cell cycle, survival, transcription, translation and ribosome biogenesis ontologies. Specifically, knockdown of AIB1 decreased ribosome-bound mRNA and steady-state protein levels of the transcription factors ERα and E2F1 in addition to reduced ribosome-bound mRNA of the ribosome biogenesis factor BYSL in a cell-line specific manner to regulate mRNA translation. CONCLUSION: The oncogenic transcription factor AIB1 has a novel role in the regulation of polyribosome recruitment and formation of the translational complex. Combinatorial therapies targeting IGF signaling and mRNA translation in AIB1 expressing breast cancers may have clinical benefit and warrants further investigation.

Asunto(s)

Neoplasias de la Mama/genética , Factor I del Crecimiento Similar a la Insulina/genética , Coactivador 3 de Receptor Nuclear/genética , Biosíntesis de Proteínas , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Neoplasias de la Mama/patología , Proteínas de Ciclo Celular , Receptor alfa de Estrógeno/genética , Factor 4E Eucariótico de Iniciación/biosíntesis , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Células MCF-7 , Fosfoproteínas/biosíntesis , Fosforilación , Proteínas Quinasas S6 Ribosómicas 70-kDa/biosíntesis , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/biosíntesis

RESUMEN

The type I insulin-like growth factor receptor (IGF1R) contributes to cancer cell biology. Disruption of IGF1R signaling alone or in combination with cytotoxic agents has emerged as a new therapeutic strategy. Our laboratory has shown that sequential treatment with doxorubicin (DOX) and anti-IGF1R antibodies significantly enhanced the response to chemotherapy. In this study, we examined whether inhibition of the tyrosine kinase activity of this receptor family would also enhance chemotherapy response. Cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) inhibited IGF1R and insulin receptor (InsR) kinase activity and downstream activation of ERK1/2 and Akt in MCF-7 and LCC6 cancer cells. PQIP inhibited both monolayer growth and anchorage-independent growth in a dose-dependent manner. PQIP did not induce apoptosis, but rather, PQIP treatment was associated with an increase in autophagy. We examined whether sequential or combination therapy of PQIP with DOX could enhance growth inhibition. PQIP treatment together with DOX or DOX followed by PQIP significantly inhibited anchorage-independent growth in MCF-7 and LCC6 cells compared to single agent alone. In contrast, pre-treatment with PQIP followed by DOX did not enhance the cytotoxicity of DOX in vitro. Furthermore, OSI-906, a PQIP derivative, inhibited IGF-I signaling in LCC6 xenograft tumors in vivo. When given once a week, simultaneous administration of OSI-906 and DOX significantly enhanced the anti-tumor effect of DOX. In summary, these results suggest that timing and duration of the IGF1R/InsR tyrosine kinase inhibitors with chemotherapeutic agents should be evaluated in clinical trials. Long-term disruption of IGF1R/InsR may not be necessary when combined with cytotoxic chemotherapy.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor de Insulina/antagonistas & inhibidores , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Autofagia/efectos de los fármacos , Neoplasias de la Mama/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Sinergismo Farmacológico , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/farmacología , Concentración 50 Inhibidora , Ratones , Ratones Desnudos , Pirazinas/administración & dosificación , Pirazinas/farmacología , Transducción de Señal/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

The oncogene amplified in breast cancer 1 (AIB1) is a nuclear receptor coactivator that plays a major role in the progression of various cancers. We previously identified a splice variant of AIB1 called AIB1-Δ4 that is overexpressed in breast cancer. Using mass spectrometry, we define the translation initiation of AIB1-Δ4 at Met(224) of the full-length AIB1 sequence and have raised an antibody to a peptide representing the acetylated N terminus. We show that AIB1-Δ4 is predominantly localized in the cytoplasm, although leptomycin B nuclear export inhibition demonstrates that AIB1-Δ4 can enter and traffic through the nucleus. Our data indicate an import mechanism enhanced by other coactivators such as p300/CBP. We report that the endogenously and exogenously expressed AIB1-Δ4 is recruited as efficiently as full-length AIB1 to estrogen-response elements of genes, and it enhances estrogen-dependent transcription more effectively than AIB1. Expression of an N-terminal AIB1 protein fragment, which is lost in the AIB1-Δ4 isoform, potentiates AIB1 as a coactivator. This suggests a model whereby the transcriptional activity of AIB1 is squelched by a repressive mechanism utilizing the N-terminal domain and that the increased coactivator function of AIB1-Δ4 is due to the loss of this inhibitory domain. Finally, we show, using Scorpion primer technology, that AIB1-Δ4 expression is correlated with metastatic capability of human cancer cell lines.

Asunto(s)

Núcleo Celular/metabolismo , Coactivador 3 de Receptor Nuclear/metabolismo , Transcripción Genética , Transporte Activo de Núcleo Celular/efectos de los fármacos , Animales , Antibióticos Antineoplásicos/farmacología , Células CHO , Células COS , Núcleo Celular/genética , Chlorocebus aethiops , Cricetinae , Cricetulus , Citoplasma/genética , Citoplasma/metabolismo , Perros , Ácidos Grasos Insaturados/farmacología , Células HEK293 , Humanos , Ratones , Coactivador 3 de Receptor Nuclear/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estructura Terciaria de Proteína , Elementos de Respuesta/genética

RESUMEN

Overexpression and activation of the steroid receptor coactivator amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) have been shown to have a critical role in oncogenesis and are required for both steroid and growth factor signaling in epithelial tumors. Here, we report a new mechanism for activation of SRC coactivators. We demonstrate regulated tyrosine phosphorylation of AIB1/SRC-3 at a C-terminal tyrosine residue (Y1357) that is phosphorylated after insulin-like growth factor 1, epidermal growth factor, or estrogen treatment of breast cancer cells. Phosphorylated Y1357 is increased in HER2/neu (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2) mammary tumor epithelia and is required to modulate AIB1/SRC-3 coactivation of estrogen receptor alpha (ERalpha), progesterone receptor B, NF-kappaB, and AP-1-dependent promoters. c-Abl (v-Abl Abelson murine leukemia viral oncogene homolog 1) tyrosine kinase directly phosphorylates AIB1/SRC-3 at Y1357 and modulates the association of AIB1 with c-Abl, ERalpha, the transcriptional cofactor p300, and the methyltransferase coactivator-associated arginine methyltransferase 1, CARM1. AIB1/SRC-3-dependent transcription and phenotypic changes, such as cell growth and focus formation, can be reversed by an Abl kinase inhibitor, imatinib. Thus, the phosphorylation state of Y1357 can function as a molecular on/off switch and facilitates the cross talk between hormone, growth factor, and intracellular kinase signaling pathways in cancer.

Asunto(s)

Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Histona Acetiltransferasas/metabolismo , Fosfotirosina/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Transactivadores/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Factor de Crecimiento Epidérmico/farmacología , Femenino , Proteínas de Fusión bcr-abl , Humanos , Factor I del Crecimiento Similar a la Insulina/farmacología , Ratones , Coactivador 3 de Receptor Nuclear , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , Mapeo de Interacción de Proteínas , Factores de Transcripción/metabolismo

RESUMEN

The steroid receptor coactivator amplified in breast cancer 1 (AIB1) as well as epidermal growth factor receptor (EGFR) family members are frequently overexpressed in epithelial tumors, and their expression is associated with poor prognosis. However, a direct role of AIB1 in EGF signaling has not been determined. To address this, we reduced endogenous AIB1 levels using RNA interference in lung, breast, and pancreatic cancer cell lines. We found that a knockdown of AIB1 levels resulted in a loss of the growth response of these cell lines to EGF. Further analysis revealed that the depletion of AIB1 reduced tyrosine phosphorylation of EGFR at multiple residues both at autophosphorylation and Src kinase phosphorylation sites. AIB1 knockdown did not affect tyrosine phosphorylation of the receptor tyrosine kinases, platelet-derived growth factor receptor and HER3, or overall tyrosine phosphorylation of cellular proteins. However, EGF-dependent phosphorylation of HER2 was decreased. EGFR levels and membrane trafficking were not changed by AIB1 depletion, but there was less recruitment of Src homology 2 domain-containing proteins to the EGFR. This led to a substantial reduction in EGF-induced phosphorylation of signal transducers and activators of transcription 5 and c-Jun NH(2)-terminal kinase but no significant change in the activation of AKT. Vanadate treatment of cells revealed that the reduction in EGFR tyrosine phosphorylation is dependent in part on changes in cellular phosphatase activity. We propose that a portion of the oncogenic effect of AIB1 could be through control of EGFR and HER2 activity and subsequent modulation of cellular signaling pathways.

Asunto(s)

Neoplasias de la Mama/metabolismo , Receptores ErbB/metabolismo , Histona Acetiltransferasas/metabolismo , Transducción de Señal , Transactivadores/metabolismo , Tirosina/metabolismo , Western Blotting , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/genética , Citometría de Flujo , Histona Acetiltransferasas/antagonistas & inhibidores , Histona Acetiltransferasas/genética , Humanos , Inmunoprecipitación , Coactivador 3 de Receptor Nuclear , Fosforilación , ARN Interferente Pequeño/farmacología , Receptor ErbB-3/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transactivadores/antagonistas & inhibidores , Transactivadores/genética

RESUMEN

The steroid receptor coactivator oncogene, amplified in breast cancer 1 (AIB1; also known as ACTR/RAC-3/TRAM-1/SRC-3/p/CIP), is amplified and overexpressed in a variety of epithelial tumors. AIB1 has been reported to have roles in both steroid-dependent and steroid-independent transcription during tumor progression. In this report, we describe that the cellular levels of AIB1 are controlled through regulated proteasomal degradation. We found that serum withdrawal or growth in high cell density caused rapid degradation of AIB1 protein, but not mRNA, in immortalized cell lines. Proteasome inhibitors prevented this process, and high molecular weight ubiquitylated species of AIB1 were detected. Nuclear export was required for proteasomal degradation of AIB1 and involved the ubiquitin ligase, E6AP. AIB1/E6AP complexes were detected in cellular extracts, and reduction of cellular E6AP levels with E6AP short interfering RNA prevented proteasomal degradation of AIB1. Conversely, overexpression of E6AP promoted AIB1 degradation. The COOH terminus of AIB1 interacted with E6AP in vitro and deletion of this region in AIB1 rendered it resistant to degradation in cells. From our results, we propose a model whereby signals promoted by changes in the cellular milieu initiate E6AP-mediated proteasomal degradation of AIB1 and thus contribute to the control of steady-state levels of this protein.

Asunto(s)

Neoplasias de la Mama/fisiopatología , Histona Acetiltransferasas/genética , Transactivadores/genética , Ubiquitina-Proteína Ligasas/fisiología , Neoplasias de la Mama/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/fisiopatología , Línea Celular , Línea Celular Transformada , Línea Celular Tumoral , Medio de Cultivo Libre de Suero , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Riñón , Coactivador 3 de Receptor Nuclear , Plásmidos , Complejo de la Endopetidasa Proteasomal/metabolismo , ARN Interferente Pequeño/genética , Transfección , Ubiquitina/genética

RESUMEN

Amplified in breast cancer 1 (AIB1, also known as ACTR, SRC-3, RAC-3, TRAM-1, p/CIP) is a member of the p160 nuclear receptor coactivator family involved in transcriptional regulation of genes activated through steroid receptors, such as estrogen receptor alpha (ER(alpha)). The AIB1 gene and a more active N-terminally deleted isoform (AIB1-Delta3) are overexpressed in breast cancer. To determine the role of AIB1-Delta3 in breast cancer pathogenesis, we generated transgenic mice with human cytomegalovirus immediate early gene 1 (hCMVIE1) promoter-driven over-expression of human AIB1/ACTR-Delta3 (CMVAIB1/ACTR-Delta3 mice). AIB1/ACTR-Delta3 transgene mRNA expression was confirmed in CMV-AIB1/ACTR-Delta3 mammary glands by in situ hybridization. These mice demonstrated significantly increased mammary epithelial cell proliferation (P < 0.003), cyclin D1 expression (P = 0.002), IGF-I receptor protein expression (P = 0.026), mammary gland mass (P < 0.05), and altered expression of CCAAT/enhancer binding protein isoforms (P = 0.029). At 13 months of age, mammary ductal ectasia was found in CMV-AIB1/ACTR-Delta3 mice, but secondary and tertiary branching patterns were normal. There were no changes in the expression patterns of either ER(alpha) or Stat5a, a downstream mediator of prolactin signaling. Serum IGF-I levels were not altered in the transgenic mice. These data indicate that overexpression of the AIB1/ACTR-Delta3 isoform resulted in altered mammary epithelial cell growth. The observed changes in cell proliferation and gene expression are consistent with alterations in growth factor signaling that are thought to contribute to either initiation or progression of breast cancer. These results are consistent with the hypothesis that the N-terminally deleted isoform of AIB1 can play a role in breast cancer development and/or progression.

Asunto(s)

Factores de Transcripción/química , Empalme Alternativo , Animales , Antígenos Virales/genética , Southern Blotting , Western Blotting , Neoplasias de la Mama/embriología , Proliferación Celular , Ciclina D1/metabolismo , ADN/metabolismo , Proteínas de Unión al ADN/química , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/metabolismo , Receptor alfa de Estrógeno/metabolismo , Regulación de la Expresión Génica , Genotipo , Humanos , Proteínas Inmediatas-Precoces/genética , Immunoblotting , Inmunohistoquímica , Hibridación in Situ , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Factor I del Crecimiento Similar a la Insulina/metabolismo , Glándulas Mamarias Animales , Glándulas Mamarias Humanas/metabolismo , Neoplasias Mamarias Animales , Ratones , Ratones Transgénicos , Proteínas de la Leche/química , Modelos Genéticos , Coactivador 3 de Receptor Nuclear , Regiones Promotoras Genéticas , Isoformas de Proteínas , Receptor IGF Tipo 1/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT5 , Transducción de Señal , Transactivadores/química , Factores de Transcripción/biosíntesis , Transgenes , Proteínas Supresoras de Tumor

RESUMEN

The nuclear receptor coactivator AIB1 (amplified in breast cancer 1) is overexpressed in human breast cancers and is required for estrogen signaling. However, the role of AIB1 in breast cancer etiology is not known. Here, we show that AIB1 is rate-limiting for insulin-like growth factor I (IGF-I)-dependent phenotypic changes and gene expression in human breast cancer cells. Reduction of endogenous AIB1 levels by small interfering RNA in MCF-7 breast cancer cells prevented IGF-I-stimulated anchorage-independent growth by reducing IGF-I-dependent anti-anoikis. cDNA array and immunoblot analysis of gene expression revealed that reduction in AIB1 levels led to a significant decrease in the expression of several genes controlling the cell cycle and apoptosis. These AIB1-dependent changes were also observed in the presence of estrogen antagonist and were corroborated in the estrogen receptor-negative cell line MDA MB-231. AIB1 reduction decreased the expression of the IGF-I receptor and IRS-1 in MCF-7 but not in MDA MB-231 cells. IGF-I-stimulated activation of AKT was reduced by AIB1 small interfering RNA treatment, whereas mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) activation by IGF-I was unaffected. We conclude that AIB1 is required for IGF-I-induced proliferation, signaling, cell survival, and gene expression in human breast cancer cells, independent of its role in estrogen receptor signaling.

Asunto(s)

Neoplasias de la Mama/metabolismo , Factor I del Crecimiento Similar a la Insulina/fisiología , Factores de Transcripción/fisiología , Secuencia de Bases , Neoplasias de la Mama/patología , Línea Celular Tumoral , Cartilla de ADN , ADN Complementario , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Coactivador 3 de Receptor Nuclear , Fenotipo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal

RESUMEN

The nuclear receptor coactivator amplified in breast cancer 1 (AIB1) and its more active isoform AIB1-Delta3 are overexpressed in breast cancer and preneoplastic breast tissue. However, the impact of these proteins on the transcriptional activity of natural estrogens or selective estrogen receptor modulators (SERMs) has not been determined. Here we show that AIB1-Delta3 causes a significant increase in the efficacy of 17beta-estradiol at both estrogen receptor-alpha (ER-alpha) and ER-beta in ovarian, breast and endometrial cancer cell lines. AIB1-Delta3 also significantly increased the efficacy of the natural estrogen genistein at both ER-alpha and ER-beta, whereas AIB1 had no effect on either the potency or efficacy of genistein at either receptor. The estrogenic efficacy of the partial agonist tamoxifen was significantly increased in all cell lines at ER-alpha by overexpression of AIB1-Delta3 both on transfected and endogenous estrogen responsive genes. In contrast, overexpression of AIB1 or AIB1-Delta3 had no effect on the potency or efficacy of the SERM raloxifene. We conclude that overexpression of the AIB1-Delta3 isoform will increase the estrogenicity of a variety of natural and pharmacologic compounds in tissues that develop hormone-dependent neoplasias and overexpression of these cofactors may be a contributing factor to the hormone-driven development of neoplasia and to antiestrogen resistance of breast cancers.

Asunto(s)

Moduladores de los Receptores de Estrógeno/farmacología , Regulación Neoplásica de la Expresión Génica , Receptores de Estrógenos/metabolismo , Factores de Transcripción/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Estradiol/metabolismo , Estradiol/farmacología , Antagonistas de Estrógenos/metabolismo , Antagonistas de Estrógenos/farmacología , Moduladores de los Receptores de Estrógeno/metabolismo , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genisteína/farmacología , Humanos , Ligandos , Coactivador 3 de Receptor Nuclear , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Isoformas de Proteínas/metabolismo , Clorhidrato de Raloxifeno/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Tamoxifeno/farmacología