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Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4

Estrogen activity towards cancer-related pathways can impact therapeutic intervention. Recent omics data suggest possible crosstalk between estrogens/gender and MDM4, a key regulator of p53. Since MDM4 can either promote cell transformation or enhance DNA damage-sensitivity, we analysed in vivo impa...

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Autores principales: Lucà, Rossella, di Blasio, Giorgia, Gallo, Daniela, Monteleone, Valentina, Manni, Isabella, Fici, Laura, Buttarelli, Marianna, Ciolli, Germana, Pellegrino, Marsha, Teveroni, Emanuela, Maiullari, Silvia, Ciucci, Alessandra, Apollo, Alessandro, Mancini, Francesca, Gentileschi, Maria Pia, Zannoni, Gian Franco, Pontecorvi, Alfredo, Scambia, Giovanni, Moretti, Fabiola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770881/
https://www.ncbi.nlm.nih.gov/pubmed/31547268
http://dx.doi.org/10.3390/cancers11091349
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author Lucà, Rossella
di Blasio, Giorgia
Gallo, Daniela
Monteleone, Valentina
Manni, Isabella
Fici, Laura
Buttarelli, Marianna
Ciolli, Germana
Pellegrino, Marsha
Teveroni, Emanuela
Maiullari, Silvia
Ciucci, Alessandra
Apollo, Alessandro
Mancini, Francesca
Gentileschi, Maria Pia
Zannoni, Gian Franco
Pontecorvi, Alfredo
Scambia, Giovanni
Moretti, Fabiola
author_facet Lucà, Rossella
di Blasio, Giorgia
Gallo, Daniela
Monteleone, Valentina
Manni, Isabella
Fici, Laura
Buttarelli, Marianna
Ciolli, Germana
Pellegrino, Marsha
Teveroni, Emanuela
Maiullari, Silvia
Ciucci, Alessandra
Apollo, Alessandro
Mancini, Francesca
Gentileschi, Maria Pia
Zannoni, Gian Franco
Pontecorvi, Alfredo
Scambia, Giovanni
Moretti, Fabiola
author_sort Lucà, Rossella
collection PubMed
description Estrogen activity towards cancer-related pathways can impact therapeutic intervention. Recent omics data suggest possible crosstalk between estrogens/gender and MDM4, a key regulator of p53. Since MDM4 can either promote cell transformation or enhance DNA damage-sensitivity, we analysed in vivo impact of estrogens on both MDM4 activities. In Mdm4 transgenic mouse, Mdm4 accelerates the formation of fibrosarcoma and increases tumor sensitivity to cisplatin as well, thus confirming in vivo Mdm4 dual mode of action. Noteworthy, Mdm4 enhances chemo- and radio-sensitivity in male but not in female animals, whereas its tumor-promoting activity is not affected by mouse gender. Combination therapy of transgenic females with cisplatin and fulvestrant, a selective estrogen receptor degrader, was able to recover tumor cisplatin-sensitivity, demonstrating the relevance of estrogens in the observed sexual dimorphism. Molecularly, estrogen receptor-α alters intracellular localization of MDM4 by increasing its nuclear fraction correlated to decreased cell death, in a p53-independent manner. Importantly, MDM4 nuclear localization and intra-tumor estrogen availability correlate with decreased platinum-sensitivity and apoptosis and predicts poor disease-free survival in high-grade serous ovarian carcinoma. These data demonstrate estrogen ability to modulate chemo-sensitivity of MDM4-expressing tumors and to impinge on intracellular trafficking. They support potential usefulness of combination therapy involving anti-estrogenic drugs.
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spelling pubmed-67708812019-10-30 Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4 Lucà, Rossella di Blasio, Giorgia Gallo, Daniela Monteleone, Valentina Manni, Isabella Fici, Laura Buttarelli, Marianna Ciolli, Germana Pellegrino, Marsha Teveroni, Emanuela Maiullari, Silvia Ciucci, Alessandra Apollo, Alessandro Mancini, Francesca Gentileschi, Maria Pia Zannoni, Gian Franco Pontecorvi, Alfredo Scambia, Giovanni Moretti, Fabiola Cancers (Basel) Article Estrogen activity towards cancer-related pathways can impact therapeutic intervention. Recent omics data suggest possible crosstalk between estrogens/gender and MDM4, a key regulator of p53. Since MDM4 can either promote cell transformation or enhance DNA damage-sensitivity, we analysed in vivo impact of estrogens on both MDM4 activities. In Mdm4 transgenic mouse, Mdm4 accelerates the formation of fibrosarcoma and increases tumor sensitivity to cisplatin as well, thus confirming in vivo Mdm4 dual mode of action. Noteworthy, Mdm4 enhances chemo- and radio-sensitivity in male but not in female animals, whereas its tumor-promoting activity is not affected by mouse gender. Combination therapy of transgenic females with cisplatin and fulvestrant, a selective estrogen receptor degrader, was able to recover tumor cisplatin-sensitivity, demonstrating the relevance of estrogens in the observed sexual dimorphism. Molecularly, estrogen receptor-α alters intracellular localization of MDM4 by increasing its nuclear fraction correlated to decreased cell death, in a p53-independent manner. Importantly, MDM4 nuclear localization and intra-tumor estrogen availability correlate with decreased platinum-sensitivity and apoptosis and predicts poor disease-free survival in high-grade serous ovarian carcinoma. These data demonstrate estrogen ability to modulate chemo-sensitivity of MDM4-expressing tumors and to impinge on intracellular trafficking. They support potential usefulness of combination therapy involving anti-estrogenic drugs. MDPI 2019-09-12 /pmc/articles/PMC6770881/ /pubmed/31547268 http://dx.doi.org/10.3390/cancers11091349 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lucà, Rossella
di Blasio, Giorgia
Gallo, Daniela
Monteleone, Valentina
Manni, Isabella
Fici, Laura
Buttarelli, Marianna
Ciolli, Germana
Pellegrino, Marsha
Teveroni, Emanuela
Maiullari, Silvia
Ciucci, Alessandra
Apollo, Alessandro
Mancini, Francesca
Gentileschi, Maria Pia
Zannoni, Gian Franco
Pontecorvi, Alfredo
Scambia, Giovanni
Moretti, Fabiola
Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4
title Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4
title_full Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4
title_fullStr Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4
title_full_unstemmed Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4
title_short Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4
title_sort estrogens counteract platinum-chemosensitivity by modifying the subcellular localization of mdm4
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770881/
https://www.ncbi.nlm.nih.gov/pubmed/31547268
http://dx.doi.org/10.3390/cancers11091349
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