Estrogen Receptor-Beta2 (ERβ2)–Mutant p53–FOXM1 Axis: A Novel Driver of Proliferation, Chemoresistance, and Disease Progression in High Grade Serous Ovarian Cancer (HGSOC)
High grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of epithelial ovarian cancer. Prevalence (~96%) of mutant p53 is a hallmark of HGSOC. Estrogen receptor-beta (ERβ) has been reported to be another important player in HGSOC, although the pro-versus anti-tumorigenic role o...
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| Format: | Article |
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MDPI AG
2022-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/5/1120 |
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| author | Chetan C. Oturkar Nishant Gandhi Pramod Rao Kevin H. Eng Austin Miller Prashant K. Singh Emese Zsiros Kunle O. Odunsi Gokul M. Das |
| author_facet | Chetan C. Oturkar Nishant Gandhi Pramod Rao Kevin H. Eng Austin Miller Prashant K. Singh Emese Zsiros Kunle O. Odunsi Gokul M. Das |
| author_sort | Chetan C. Oturkar |
| collection | DOAJ |
| description | High grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of epithelial ovarian cancer. Prevalence (~96%) of mutant p53 is a hallmark of HGSOC. Estrogen receptor-beta (ERβ) has been reported to be another important player in HGSOC, although the pro-versus anti-tumorigenic role of its different isoforms remains unsettled. However, whether there is functional interaction between ERβ and mutant p53 in HGSOC is unknown. ERβ1 and ERβ2 mRNA and protein analysis in HGSOC cell lines demonstrated that ERβ2 is the predominant isoform in HGSOC. Specificity of ERβ2 antibody was ascertained using cells depleted of ERβ2 and ERβ1 separately with isoform-specific siRNAs. ERβ2-mutant p53 interaction in cell lines was confirmed by co-immunoprecipitation and in situ proximity ligation assay (PLA). Expression levels of ERβ2, ERα, p53, and FOXM1 proteins and ERβ2-mutant p53 interaction in patient tumors were determined by immunohistochemistry (IHC) and PLA, respectively. ERβ2 levels correlate positively with FOXM1 levels and negatively with progression-free survival (PFS) and overall survival (OS). Quantitative chromatin immunoprecipitation (qChIP) and mRNA expression analysis revealed that ERβ2 and mutant p53 co-dependently regulated <i>FOXM1</i> gene transcription. The combination of ERβ2-specific siRNA and PRIMA-1<sup>MET</sup> that converts mutant p53 to wild type conformation increased apoptosis. Our work provides the first evidence for a novel ERβ2-mutant p53-FOXM1 axis that can be exploited for new therapeutic strategies against HGSOC. |
| first_indexed | 2024-03-09T20:45:24Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T20:45:24Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-223fed3bf08a4c78ac4d893d3e9d57192023-11-23T22:46:10ZengMDPI AGCancers2072-66942022-02-01145112010.3390/cancers14051120Estrogen Receptor-Beta2 (ERβ2)–Mutant p53–FOXM1 Axis: A Novel Driver of Proliferation, Chemoresistance, and Disease Progression in High Grade Serous Ovarian Cancer (HGSOC)Chetan C. Oturkar0Nishant Gandhi1Pramod Rao2Kevin H. Eng3Austin Miller4Prashant K. Singh5Emese Zsiros6Kunle O. Odunsi7Gokul M. Das8Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USAGenomic Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USAHigh grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of epithelial ovarian cancer. Prevalence (~96%) of mutant p53 is a hallmark of HGSOC. Estrogen receptor-beta (ERβ) has been reported to be another important player in HGSOC, although the pro-versus anti-tumorigenic role of its different isoforms remains unsettled. However, whether there is functional interaction between ERβ and mutant p53 in HGSOC is unknown. ERβ1 and ERβ2 mRNA and protein analysis in HGSOC cell lines demonstrated that ERβ2 is the predominant isoform in HGSOC. Specificity of ERβ2 antibody was ascertained using cells depleted of ERβ2 and ERβ1 separately with isoform-specific siRNAs. ERβ2-mutant p53 interaction in cell lines was confirmed by co-immunoprecipitation and in situ proximity ligation assay (PLA). Expression levels of ERβ2, ERα, p53, and FOXM1 proteins and ERβ2-mutant p53 interaction in patient tumors were determined by immunohistochemistry (IHC) and PLA, respectively. ERβ2 levels correlate positively with FOXM1 levels and negatively with progression-free survival (PFS) and overall survival (OS). Quantitative chromatin immunoprecipitation (qChIP) and mRNA expression analysis revealed that ERβ2 and mutant p53 co-dependently regulated <i>FOXM1</i> gene transcription. The combination of ERβ2-specific siRNA and PRIMA-1<sup>MET</sup> that converts mutant p53 to wild type conformation increased apoptosis. Our work provides the first evidence for a novel ERβ2-mutant p53-FOXM1 axis that can be exploited for new therapeutic strategies against HGSOC.https://www.mdpi.com/2072-6694/14/5/1120high grade serous ovarian cancerestrogen receptor-beta2mutant p53FOXM1therapeutic resistancecarboplatin |
| spellingShingle | Chetan C. Oturkar Nishant Gandhi Pramod Rao Kevin H. Eng Austin Miller Prashant K. Singh Emese Zsiros Kunle O. Odunsi Gokul M. Das Estrogen Receptor-Beta2 (ERβ2)–Mutant p53–FOXM1 Axis: A Novel Driver of Proliferation, Chemoresistance, and Disease Progression in High Grade Serous Ovarian Cancer (HGSOC) Cancers high grade serous ovarian cancer estrogen receptor-beta2 mutant p53 FOXM1 therapeutic resistance carboplatin |
| title | Estrogen Receptor-Beta2 (ERβ2)–Mutant p53–FOXM1 Axis: A Novel Driver of Proliferation, Chemoresistance, and Disease Progression in High Grade Serous Ovarian Cancer (HGSOC) |
| title_full | Estrogen Receptor-Beta2 (ERβ2)–Mutant p53–FOXM1 Axis: A Novel Driver of Proliferation, Chemoresistance, and Disease Progression in High Grade Serous Ovarian Cancer (HGSOC) |
| title_fullStr | Estrogen Receptor-Beta2 (ERβ2)–Mutant p53–FOXM1 Axis: A Novel Driver of Proliferation, Chemoresistance, and Disease Progression in High Grade Serous Ovarian Cancer (HGSOC) |
| title_full_unstemmed | Estrogen Receptor-Beta2 (ERβ2)–Mutant p53–FOXM1 Axis: A Novel Driver of Proliferation, Chemoresistance, and Disease Progression in High Grade Serous Ovarian Cancer (HGSOC) |
| title_short | Estrogen Receptor-Beta2 (ERβ2)–Mutant p53–FOXM1 Axis: A Novel Driver of Proliferation, Chemoresistance, and Disease Progression in High Grade Serous Ovarian Cancer (HGSOC) |
| title_sort | estrogen receptor beta2 erβ2 mutant p53 foxm1 axis a novel driver of proliferation chemoresistance and disease progression in high grade serous ovarian cancer hgsoc |
| topic | high grade serous ovarian cancer estrogen receptor-beta2 mutant p53 FOXM1 therapeutic resistance carboplatin |
| url | https://www.mdpi.com/2072-6694/14/5/1120 |
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