Cancers, Vol. 11, Pages 1349: Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4

Cancers, Vol. 11, Pages 1349: Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4 Cancers doi: 10.3390/cancers11091349 Authors: Rossella Lucà Giorgia di Blasio Daniela Gallo Valentina Monteleone Isabella Manni Laura Fici Marianna Buttarelli Germana Ciolli Marsha Pellegrino Emanuela Teveroni Silvia Maiullari Alessandra Ciucci Alessandro Apollo Francesca Mancini Maria Pia Gentileschi Gian Franco Zannoni Alfredo Pontecorvi Giovanni Scambia Fabiola Moretti 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-&...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research