Mutant p53 negatively regulates ER? activity to drive resistance to endocrine therapy [ChIP-seq]
High-grade serous ovarian cancer (HGSOC) is a highly lethal gynecologic malignancy in women.  Women diagnosed with HGSOC initially respond to chemotherapy but there is a greater than 80% rate of relapse.  There is thus a significant unmet need for new therapeutic targets for HGSOC.  Estrogen receptor alpha (ER?) is a particularly attractive candidate, as 70-80% of HGSOC tumors stain positively for ER? and there are approved inhibitors that show limited toxicity.  Unlike the case for breast cancer however, endocrine therapy for HGSOC has not shown consistently promising results.  In this work we show that mutant forms of p53, which occur in 70% of HGSOC, inhibits ER? function and confer resistance to fulvestrant and elacestrant.  Mechanistically we show that mutant p53 only inhibits one arm of the ER? pathway: the transactivation of jointly regulated ER?-SP1 target genes, like DEPTOR, which encodes an mTOR inhibitor.  We show that silencing mutant p53 restores the ability of ER? to transactivate ER?-SP1 target genes, and renders HGSOC sensitive to endocrine therapy.  This work resolves part of the underlying reason for endocrine resistance of HGSOC, and reveals one mechanism to reverse such: refold or ablate mutant p53. Overall design: ChIP-seq analysis of ER? and SP1 in control and sip53 PEO1 cells, with or without E2 treatment.