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Mutant p53 negatively regulates ER⍺ activity to drive resistance to endocrine therapy [RNA-seq]

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 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292582 | GEO | 2026/01/28

REPOSITORIES: GEO

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Mutant p53 negatively regulates ER⍺ activity to drive resistance to endocrine therapy

Project description: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.

2026-01-28 | GSE292625 | GEO

Mutant p53 negatively regulates ER⍺ activity to drive resistance to endocrine therapy [ChIP-seq]

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Active estrogen receptor-alpha signaling in ovarian cancer

Project description:High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha (ER) in ~80% of HGSOC and some small but promising clinical trials of endocrine therapy, ER has been understudied as a target in this disease. Results: Proliferation is ER-regulated in HGSOC cells in vitro and in vivo, and is in part dependent on 3-D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as ER targets. The selective ER down-regulator (SERD) fulvestrant is more effective than tamoxifen in blocking ER action. ER H-score was predictive of efficacy of endocrine therapy, and this prediction could be further improved by inclusion of target gene expression, especially that of IGFBP3. Conclusion: Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional ER and endocrine responsiveness. Assessing ER function (e.g. IGFBP3 expression) in conjunction with ERH-score may help select patients who would benefit from endocrine therapy. Our preclinical data suggest that SERDs might be more effective than tamoxifen.

2017-05-15 | GSE81612 | GEO

Targeting SUV39H2 Exon Skipping Reversing CDK4/6 Inhibitor Resistance in Breast Cancer [RNAseq]

Project description:Breast cancer, the most prevalent malignancy among women, is predominantly estrogen receptor-positive (ER+), with ER+ cases accounting for 80% of the total. The combination of CDK4/6 inhibitors and endocrine therapy has become the standard treatment for advanced ER+ breast cancer. However, around 30% of patients exhibit intrinsic resistance, while others eventually develop acquired resistance leading to recurrence and metastasis. Here, we identified reduced exon 2 skipping of SUV39H2 in CDK4/6 inhibitor-resistant breast cancer cells, leading to increased SUV39H2 protein expression and consequent elevation of H3K9me3 levels, collectively suppressing the p53 pathway and promote resistance. Subsequently, we designed antisense oligonucleotides (ASOs) to modulate SUV39H2 exon skipping, which successfully reduced SUV39H2 levels and H3K9me3 modifications, thereby reactivating p53 target genes and restoring drug sensitivity in vitro and in vivo.Our results demonstrate that SUV39H2 serves as both a potential biomarker and therapeutic target for CDK4/6 inhibitor-resistant breast cancer, highlighting its clinical translational value.

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Targeting SUV39H2 Exon Skipping Reversing CDK4/6 Inhibitor Resistance in Breast Cancer

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Targeting SUV39H2 Exon Skipping Reversing CDK4/6 Inhibitor Resistance in Breast Cancer [CUT&Tag]

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Mutant p53 negatively regulates ER⍺ activity to drive resistance to endocrine therapy

Project description:Mutant p53 negatively regulates ER⍺ activity to drive resistance to endocrine therapy

| PRJNA1240323 | ENA

The Ashkenazi-centric G334R variant of TP53 is severely impaired for transactivation but retains tumor suppressor function in a mouse model [ChIP-Seq]

Project description:Mutations in the TP53 tumor suppressor gene are the most abundant genetic occurrences in cancer. Some of these mutations lead to loss of function of p53 protein, some are gain of function, and some variants are hypomorphic (partially-functional). Currently, there is no clinical distinction between different p53 mutations and cancer therapy or prognosis. Mutations in the oligomerization domain of p53 appear to be quite distinct in function, compared to mutations in the DNA binding domain. Here we show that, like other p53 oligomerization domain mutants, the Ashkenazi-specific G334R mutant accumulates to very high levels in cells and is significantly impaired for the transactivation of canonical p53 target genes. Surprisingly, we find that this mutant retains the ability to bind to consensus p53 target sites. A mouse model reveals that mice containing the G334R variant show increased predisposition to cancer, but only a fraction of these mice develop cancer at late onset. We show that the G334R variant retains the ability to interact with the SP1 transcription factor and contributes to the transactivation of joint SP1-p53 target genes. The combined evidence indicates that G334R is a unique oligomerization domain mutant that retains some tumor suppressor function.

2025-09-19 | GSE277586 | GEO

The Ashkenazi-centric G334R variant of TP53 is severely impaired for transactivation but retains tumor suppressor function in a mouse model [RNA-seq]

2025-09-19 | GSE277585 | GEO

Lineage specific extracellular vesicle-associated protein biomarkers for the early detection of high grade serous ovarian cancer

Project description:High grade serous ovarian carcinoma (HGSOC) accounts for ~70% of ovarian cancer cases. Non-invasive, highly specific blood-based tests for pre-symptomatic screening in women are crucial to reducing the mortality associated with this disease. Since most HGSOCs typically arise from the fallopian tubes (FT), our biomarker search focused on proteins found on the surface of extracellular vesicles (EVs) released by both FT and HGSOC tissue explants and representative cell lines. Using mass spectrometry, 985 EV proteins (exo-proteins) were identified that comprised the FT/HGSOC EV core proteome. Transmembrane exo-proteins were prioritized because these could serve as antigens for capture and/or detection. With a nano-engineered microfluidic platform, six newly discovered exo-proteins (ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF) plus a known HGSOC associated protein, FOLR1 exhibited classification performance ranging from 85-98% in a case-control study using plasma samples representative of early (including stage IA/B) and late stage (stage III) HGSOCs. Furthermore, by a linear combination of IGSF8 and ITGA5 based on logistic regression analysis, we achieved a sensitivity of 80% with 99.8% specificity and a positive predictive value of 13.8%. Importantly, these exo-proteins also can accurately discriminate between ovarian and 12 types of cancers commonly diagnosed in women. Our studies demonstrate that these lineage-associated exo-biomarkers can detect ovarian cancer with high specificity and sensitivity early and potentially while localized to the FT when patient outcomes are more favorable.

2023-10-09 | PXD036726 | Pride

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