Nuclear PRMT5 is a biomarker of sensitivity to tamoxifen in ERα+ breast cancer
Abstract Endocrine therapies targeting estrogen signaling, such as tamoxifen, have significantly improved management of estrogen receptor alpha (ERα)‐positive breast cancers. However, their efficacy is limited by intrinsic and acquired resistance to treatment, and there is currently no predictive ma...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-08-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202217248 |
| _version_ | 1797279733902213120 |
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| author | Coralie Poulard Thuy Ha Pham Youenn Drouet Julien Jacquemetton Ausra Surmielova Loay Kassem Benoite Mery Christine Lasset Jonathan Reboulet Isabelle Treilleux Elisabetta Marangoni Olivier Trédan Muriel Le Romancer |
| author_facet | Coralie Poulard Thuy Ha Pham Youenn Drouet Julien Jacquemetton Ausra Surmielova Loay Kassem Benoite Mery Christine Lasset Jonathan Reboulet Isabelle Treilleux Elisabetta Marangoni Olivier Trédan Muriel Le Romancer |
| author_sort | Coralie Poulard |
| collection | DOAJ |
| description | Abstract Endocrine therapies targeting estrogen signaling, such as tamoxifen, have significantly improved management of estrogen receptor alpha (ERα)‐positive breast cancers. However, their efficacy is limited by intrinsic and acquired resistance to treatment, and there is currently no predictive marker of response to these anti‐estrogens to guide treatment decision. Here, using two independent cohorts of breast cancer patients, we identified nuclear PRMT5 expression as an independent predictive marker of sensitivity to tamoxifen. Mechanistically, we discovered that tamoxifen stimulates ERα methylation by PRMT5, a key event for its binding to corepressors such as SMRT and HDAC1, participating in the inhibition of the transcriptional activity of ERα. Although PRMT5 is mainly localized in the cytoplasm of tumor cells, our analyses show that tamoxifen triggers its nuclear translocation in tamoxifen‐sensitive tumors but not in resistant ones. Hence, we unveil a biomarker of sensitivity to tamoxifen in ERα‐positive breast tumors that could be used to enhance the response of breast cancer patients to endocrine therapy, by fostering its nuclear expression. |
| first_indexed | 2024-03-07T16:30:15Z |
| format | Article |
| id | doaj.art-26bc168fc37e4a74ac05932309583845 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:30:15Z |
| publishDate | 2023-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-26bc168fc37e4a74ac059323095838452024-03-03T10:44:42ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-08-01158n/an/a10.15252/emmm.202217248Nuclear PRMT5 is a biomarker of sensitivity to tamoxifen in ERα+ breast cancerCoralie Poulard0Thuy Ha Pham1Youenn Drouet2Julien Jacquemetton3Ausra Surmielova4Loay Kassem5Benoite Mery6Christine Lasset7Jonathan Reboulet8Isabelle Treilleux9Elisabetta Marangoni10Olivier Trédan11Muriel Le Romancer12Université de Lyon Lyon FranceUniversité de Lyon Lyon FranceDépartement Prévention et Santé Publique Centre Léon Bérard Lyon FranceUniversité de Lyon Lyon FranceUniversité de Lyon Lyon FranceClinical Oncology Department, Faculty of Medicine Cairo University Cairo EgyptUniversité de Lyon Lyon FranceDépartement Prévention et Santé Publique Centre Léon Bérard Lyon FranceLipics Services Lyon FranceUniversité de Lyon Lyon FranceTranslational Research Department Institut Curie Paris FranceUniversité de Lyon Lyon FranceUniversité de Lyon Lyon FranceAbstract Endocrine therapies targeting estrogen signaling, such as tamoxifen, have significantly improved management of estrogen receptor alpha (ERα)‐positive breast cancers. However, their efficacy is limited by intrinsic and acquired resistance to treatment, and there is currently no predictive marker of response to these anti‐estrogens to guide treatment decision. Here, using two independent cohorts of breast cancer patients, we identified nuclear PRMT5 expression as an independent predictive marker of sensitivity to tamoxifen. Mechanistically, we discovered that tamoxifen stimulates ERα methylation by PRMT5, a key event for its binding to corepressors such as SMRT and HDAC1, participating in the inhibition of the transcriptional activity of ERα. Although PRMT5 is mainly localized in the cytoplasm of tumor cells, our analyses show that tamoxifen triggers its nuclear translocation in tamoxifen‐sensitive tumors but not in resistant ones. Hence, we unveil a biomarker of sensitivity to tamoxifen in ERα‐positive breast tumors that could be used to enhance the response of breast cancer patients to endocrine therapy, by fostering its nuclear expression.https://doi.org/10.15252/emmm.202217248arginine methylationestrogen receptorPRMT5resistancetamoxifen |
| spellingShingle | Coralie Poulard Thuy Ha Pham Youenn Drouet Julien Jacquemetton Ausra Surmielova Loay Kassem Benoite Mery Christine Lasset Jonathan Reboulet Isabelle Treilleux Elisabetta Marangoni Olivier Trédan Muriel Le Romancer Nuclear PRMT5 is a biomarker of sensitivity to tamoxifen in ERα+ breast cancer EMBO Molecular Medicine arginine methylation estrogen receptor PRMT5 resistance tamoxifen |
| title | Nuclear PRMT5 is a biomarker of sensitivity to tamoxifen in ERα+ breast cancer |
| title_full | Nuclear PRMT5 is a biomarker of sensitivity to tamoxifen in ERα+ breast cancer |
| title_fullStr | Nuclear PRMT5 is a biomarker of sensitivity to tamoxifen in ERα+ breast cancer |
| title_full_unstemmed | Nuclear PRMT5 is a biomarker of sensitivity to tamoxifen in ERα+ breast cancer |
| title_short | Nuclear PRMT5 is a biomarker of sensitivity to tamoxifen in ERα+ breast cancer |
| title_sort | nuclear prmt5 is a biomarker of sensitivity to tamoxifen in erα breast cancer |
| topic | arginine methylation estrogen receptor PRMT5 resistance tamoxifen |
| url | https://doi.org/10.15252/emmm.202217248 |
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