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.