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  • Title: p53 status influences response to tamoxifen but not to fulvestrant in breast cancer cell lines.
    Author: Fernandez-Cuesta L, Anaganti S, Hainaut P, Olivier M.
    Journal: Int J Cancer; 2011 Apr 15; 128(8):1813-21. PubMed ID: 20549698.
    Abstract:
    Mutations in the tumor suppressor gene TP53 are associated with poor prognosis in breast cancer. This prognostic value may rely in part on the fact that p53 plays a role in the antiproliferative and apoptotic activities of chemotherapy regimens used to treat breast tumors. However, some studies suggested that p53 may also influence response to antihormone treatments. Here we investigate how p53 may affect response to antihormonal treatments, using estrogen-dependent breast cancer cell-lines with different p53 status. We show that p53 mutated cells were more resistant to cytotoxic effects of 4-hydroxy-tamoxifen (OHT) compared to p53 wild-type cells. In contrast, p53 status did not significantly impact on response to fulvestrant. p53 mutated cells were also hypersensitive to proliferative effects of estradiol. Interestingly, OHT at doses in the low range had proliferative activities in p53 mutated cells (120-150% proliferation rate under 1 μM OHT treatment in low estrogen conditions). Using gene silencing or specific tyrosine kinase inhibitors, we show that the proliferative effects of OHT were estrogen receptor dependent and could be abrogated by the inhibition of EGFR and/or HER2 kinases. These findings suggest that loss of p53 function may increase cross-talks between estrogen receptor and EGFR/HER2 pathways, contributing to a proliferative effect of OHT. These results bring new insights into the prognostic role of p53 in breast cancer and into possible mechanisms underlying tamoxifen resistance.
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