Resistencia constitutiva y adquirida al tratamiento hormonal de carcinomas mamarios murinos
The mechanisms by which estrogens and progestins activate estrogen (ER) and progesterone receptors (PR) respectively are still a main and controversial area in breast cancer research. The detection of these receptors is used as a prognostic factor and patients with high levels of ER and PR will be t...
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| Otros Autores: | , , , , |
| Formato: | Tesis Libro |
| Lenguaje: | Español |
| Publicado: |
2010
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| Materias: | |
| Acceso en línea: | Registro en la Biblioteca Digital Handle |
| Aporte de: | Registro referencial: Solicitar el recurso aquí |
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| 084 | |a BIO 004744 | ||
| 100 | 1 | |a Wargon, Victoria |g wargon@dna.uba.ar |4 aut |e autor | |
| 245 | 1 | 0 | |a Resistencia constitutiva y adquirida al tratamiento hormonal de carcinomas mamarios murinos |
| 246 | 3 | 1 | |a Constitutive and acquired hormone resistance in murine breast carcinomas |
| 260 | |c 2010 | ||
| 300 | |a xx, 187 h. : |b il. | ||
| 502 | |b Doctor de la Universidad de Buenos Aires en el área de Ciencias Biológicas |c Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales (FCEN-UBA) |d 2010 |g Instituto de Biología y Medicina Experimental | ||
| 506 | 0 | |e Autorización del autor |f info:eu-repo/semantics/openAccess |2 openaire | |
| 518 | |d 2011-11-10 |o Fecha de publicación en la Biblioteca Digital FCEN-UBA | ||
| 520 | 3 | |a The mechanisms by which estrogens and progestins activate estrogen (ER) and progesterone receptors (PR) respectively are still a main and controversial area in breast cancer research. The detection of these receptors is used as a prognostic factor and patients with high levels of ER and PR will be treated with a hormone therapy aimed to block estrogen synthesis or to inhibit ER activation. There is however compelling evidence that points out that PR is also involved in the development and progression of breast carcinomas. In our Laboratory we have developed an experimental model of mammary carcinomas induced by the continuous administration of medroxyprogesterone acetate (MPA) into BALB/c female mice. MPA-dependent tumors (HD) are maintained by syngeneic transplantations in MPA-treated mice. Spontaneously, tumors which are able to grow without exogenous hormone supply may arise, and these are referred to as hormone independent tumors (HI). Both tumor types express ER alpha (ERα) and beta (ERβ), and both isoforms of PR (PRA and PRB). HI tumors are classified as antiprogestin responsive or antiprogestins resistant tumors. We have already demonstrated that PR play a key role mediating tumor growth in both tumor types since antisense oligonucleotides of PR and different antiprogestins inhibit their growth. In this study we analyzed 3 responsive, 3 acquired resistant and 2 constitutive resistant tumors from three different tumor families from the MPA breast cancer model. We demonstrated that the difference between these responsive and resistant tumors relies in the PRA/PRB ratio, being PRA higher than PRB in responsive tumors. Interestingly the acquired resistant phenotype was possible to be reverted and this reversion was significantly associated with an increase in PRA expression. We demonstrated that only in the constitutive-resistant tumors, PRA expression was silenced by DNA methylation. This prompted us to investigate whether the treatment of constitutive resistant tumors with a demethylating agent could restore PRA expression and antiprogestins responsiveness. We found that 5-aza- 2 ́-deoxycytidine treatment induced PRA expression and RU-486 responsiveness in vitro and in vivo experiments. Furthermore, high levels of DNA methyltransferase (Dnmts) were detected in these tumors. In conclusion, our results suggest that methyltransferase inhibitors in combination with antiprogestins may be effective in the treatment of constitutive-resistant carcinomas with a high DNA methyltransferase level. The correlation between PRA expression and antiprogestins responsiveness supports the hypothesis that antiprogestin should be used for the treatment of breast cancer patients showing high expression of PRA. |l eng | |
| 520 | 3 | |a Los mecanismos por los cuales los estrógenos y los progestágenos, a través de sus respectivos receptores (RE y RP), participan en el desarrollo y crecimiento del cáncer de mama es un tema de gran interés ya que su detección se utiliza como factor pronóstico y orienta la terapéutica hacia una de tipo hormonal. En nuestro laboratorio se ha desarrollado un modelo experimental de adenocarcinomas mamarios murinos inducidos por acetato de medroxiprogesterona (MPA) en ratones hembras vírgenes de la cepa BALB/c. Se establecieron líneas tumorales hormono-dependientes (HD) y hormono-independientes (HI) que expresan RE, alfa (REα) y beta (REβ), y las dos isoformas del RP (RPA y RPB). Los tumores HI se clasifican en respondedores (sensibles) y resistentes a la terapia con antiprogestágenos. Hemos generado a su vez por presión selectiva variantes tumorales con resistencia adquirida a los mismos. Utilizando tres familias tumorales de este modelo, demostramos que los tumores sensibles expresan mayor nivel de RPA que de RPB, mientras que lo opuesto se observa en los resistentes. Esta diferencia sería un posible marcador para discriminar un tumor sensible de uno resistente. Pudimos determinar que la resistencia adquirida puede revertir ya sea por tratamiento hormonal, o por cultivo y en todos los casos esta reversión se ve acompañada de la reexpresión de RPA. Demostramos que el silenciamiento de RPA en los tumores con resistencia adquirida se debe a metilación del promotor de PRA y que el tratamiento con el agente desmetilante 5azadC desensibiliza los tumores al antiprogestágeno. No hemos podido hasta el momento dilucidar cuál es el mecanismo que silencia la expresión de RPA en los tumores con resistencia adquirida, sin embargo la plasticidad que observamos en la expresión de esta isoforma nos hace pensar que se trataría de algún otro mecanismo epigenético. La fuerte correlación que hemos observado a lo largo de este trabajo de investigación entre la expresión de RPA y la sensibilidad a los antiprogestágenos sugieren que la terapia con antiprogestágenos debería ser considerada como posible tratamiento para tumores de mama con alta expresión de RPA. |l spa | |
| 540 | |f https://creativecommons.org/licenses/by-nc-sa/2.5/ar |2 cc | ||
| 562 | |e 1 ej. | ||
| 653 | 1 | 0 | |a RESISTENCIA HORMONAL ADQUIRIDA |
| 653 | 1 | 0 | |a AKT |
| 653 | 1 | 0 | |a ANTIPROGESTAGENOS |
| 653 | 1 | 0 | |a CANCER DE MAMA |
| 653 | 1 | 0 | |a RESISTENCIA HORMONAL CONSTITUTIVA |
| 653 | 1 | 0 | |a ERK |
| 653 | 1 | 0 | |a METASTASIS |
| 653 | 1 | 0 | |a ISOFORMAS DEL RECEPTOR DE PROGESTERONA |
| 653 | 1 | 0 | |a METILACION |
| 653 | 1 | 0 | |a INHIBIDORES DE LAS DNMTS |
| 654 | 1 | |c G |b biología |a biología molecular y celular |2 fcen-bd | |
| 654 | 1 | |c G |b biología |a biomedicina |2 fcen-bd | |
| 690 | 1 | 0 | |a ACQUIRED HORMONE RESISTANCE |
| 690 | 1 | 0 | |a AKT |
| 690 | 1 | 0 | |a ANTIPROGESTINS |
| 690 | 1 | 0 | |a BREAST CANCER |
| 690 | 1 | 0 | |a DE NOVO HORMONE-RESISTANCE |
| 690 | 1 | 0 | |a ERK |
| 690 | 1 | 0 | |a METASTASIS |
| 690 | 1 | 0 | |a PROGESTERONE RECEPTOR ISOFORMS |
| 690 | 1 | 0 | |a TUMOR REGRESSION |
| 690 | 1 | 0 | |a DNA-METHYLATION |
| 690 | 1 | 0 | |a DNMT INHIBITORS |
| 691 | 7 | |2 fcen-at |a biologia | |
| 700 | 1 | |a Lanari, Claudia Lee Malvina |4 ths |e dir | |
| 700 | 1 | |a Muschietti, Jorge |e cons | |
| 700 | 1 | |a Calvo, Juan Carlos |e jurado | |
| 700 | 1 | |a Vázquez, Elba Susana |e jurado | |
| 700 | 1 | |a Galigniana, Mario Daniel |e jurado | |
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