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Updated: Jan 12, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Mutant p53 binds and controls estrogen receptor activity to drive endocrine resistance in ovarian cancer
Chunlei Shao1, Alexandra Indeglia1, Maya Foster1,2
1Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Abstract:
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 >80% rate of relapse. There is thus a significant unmet need for new therapeutic targets for HGSOC. Estrogen receptor α (ERα) is a particularly attractive candidate, as ∼70% of HGSOC tumors stain positively for ERα and there are approved inhibitors that show limited toxicity. However, unlike the case for breast cancer, endocrine therapy for HGSOC has not shown consistently promising results. In this work, we show that missense mutant forms of p53, which occur in >60% of HGSOC, bind and inhibit ERα function and confer resistance to fulvestrant and elacestrant. Mechanistically, we show that mutant p53 predominantly inhibits one arm of the ERα pathway-the transactivation of jointly regulated ERα-SP1 target genes such as the mTOR regulator DEPTOR We show that silencing mutant p53 restores the ability of ERα to transactivate ERα-SP1 target genes and renders HGSOC markedly more sensitive to endocrine therapy. Consistent with this premise, we show that the p53 mutant Y220C refolding compound rezatapopt enhances fulvestrant response in a Y220C mutant cell line.
Insights
Mutant p53 hinders estrogen receptor alpha (ERα) in ovarian cancer, causing endocrine therapy resistance. Silencing mutant p53 restores ERα function, improving treatment sensitivity in high-grade serous ovarian cancer (HGSOC).
Area of Science:
- Gynecologic Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- High-grade serous ovarian cancer (HGSOC) has a high mortality rate with frequent relapse after chemotherapy.
- Estrogen receptor alpha (ERα) is present in ~70% of HGSOC tumors, suggesting potential for endocrine therapy.
- Current endocrine therapies for HGSOC show limited efficacy, indicating a need for novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of mutant p53 in ERα function and endocrine therapy resistance in HGSOC.
- To explore the mechanism by which mutant p53 affects ERα signaling.
- To evaluate the therapeutic potential of targeting mutant p53 or restoring ERα activity.
Main Methods:
- Analysis of mutant p53 binding to ERα in HGSOC cells.
- Assessment of ERα-SP1 target gene transactivation in the presence and absence of mutant p53.
- Evaluation of HGSOC sensitivity to endocrine therapy after mutant p53 silencing.
- Testing the efficacy of a p53 mutant Y220C refolding compound (rezatapopt) in combination with fulvestrant.
Main Results:
- Missense mutant p53 directly binds and inhibits ERα activity in HGSOC.
- Mutant p53 confers resistance to endocrine therapies like fulvestrant and elacestrant.
- Mutant p53 specifically blocks ERα-SP1 target gene transactivation, including DEPTOR, an mTOR regulator.
- Silencing mutant p53 restores ERα function and sensitizes HGSOC to endocrine therapy.
- Rezatapopt enhances fulvestrant response in a Y220C mutant cell line.
Conclusions:
- Mutant p53 is a key driver of endocrine therapy resistance in HGSOC by inhibiting ERα.
- Targeting mutant p53 or restoring ERα signaling presents a promising therapeutic avenue for HGSOC.
- Combination strategies involving endocrine therapy and mutant p53 modulators warrant further clinical investigation.
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