Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers
Abstract TNBC is a highly heterogeneous and aggressive breast cancer subtype associated with high relapse rates, and for which no targeted therapy yet exists. Protein arginine methyltransferase 5 (PRMT5), an enzyme which catalyzes the methylation of arginines on histone and non‐histone proteins, has...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-05-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.2114 |
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| author | Mathilde Vinet Samyuktha Suresh Virginie Maire Clarisse Monchecourt Fariba Némati Laetitia Lesage Fabienne Pierre Mengliang Ye Auriane Lescure Amélie Brisson Didier Meseure André Nicolas Guillem Rigaill Elisabetta Marangoni Elaine Del Nery Sergio Roman‐Roman Thierry Dubois |
| author_facet | Mathilde Vinet Samyuktha Suresh Virginie Maire Clarisse Monchecourt Fariba Némati Laetitia Lesage Fabienne Pierre Mengliang Ye Auriane Lescure Amélie Brisson Didier Meseure André Nicolas Guillem Rigaill Elisabetta Marangoni Elaine Del Nery Sergio Roman‐Roman Thierry Dubois |
| author_sort | Mathilde Vinet |
| collection | DOAJ |
| description | Abstract TNBC is a highly heterogeneous and aggressive breast cancer subtype associated with high relapse rates, and for which no targeted therapy yet exists. Protein arginine methyltransferase 5 (PRMT5), an enzyme which catalyzes the methylation of arginines on histone and non‐histone proteins, has recently emerged as a putative target for cancer therapy. Potent and specific PRMT5 inhibitors have been developed, but the therapeutic efficacy of PRMT5 targeting in TNBC has not yet been demonstrated. Here, we examine the expression of PRMT5 in a human breast cancer cohort obtained from the Institut Curie, and evaluate the therapeutic potential of pharmacological inhibition of PRMT5 in TNBC. We find that PRMT5 mRNA and protein are expressed at comparable levels in TNBC, luminal breast tumors, and healthy mammary tissues. However, immunohistochemistry analyses reveal that PRMT5 is differentially localized in TNBC compared to other breast cancer subtypes and to normal breast tissues. PRMT5 is heterogeneously expressed in TNBC and high PRMT5 expression correlates with poor prognosis within this breast cancer subtype. Using the small‐molecule inhibitor EPZ015666, we show that PRMT5 inhibition impairs cell proliferation in a subset of TNBC cell lines. PRMT5 inhibition triggers apoptosis, regulates cell cycle progression and decreases mammosphere formation. Furthermore, EPZ015666 administration to a patient‐derived xenograft model of TNBC significantly deters tumor progression. Finally, we reveal potentiation between EGFR and PRMT5 targeting, suggestive of a beneficial combination therapy. Our findings highlight a distinctive subcellular localization of PRMT5 in TNBC, and uphold PRMT5 targeting, alone or in combination, as a relevant treatment strategy for a subset of TNBC. |
| format | Article |
| id | doaj-art-e38d40999951432e94d1e8844dc31f54 |
| institution | Kabale University |
| issn | 2045-7634 |
| language | English |
| publishDate | 2019-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-e38d40999951432e94d1e8844dc31f542024-11-15T13:01:04ZengWileyCancer Medicine2045-76342019-05-01852414242810.1002/cam4.2114Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancersMathilde Vinet0Samyuktha Suresh1Virginie Maire2Clarisse Monchecourt3Fariba Némati4Laetitia Lesage5Fabienne Pierre6Mengliang Ye7Auriane Lescure8Amélie Brisson9Didier Meseure10André Nicolas11Guillem Rigaill12Elisabetta Marangoni13Elaine Del Nery14Sergio Roman‐Roman15Thierry Dubois16Translational Research Department Institut Curie, PSL Research University Paris FranceTranslational Research Department Institut Curie, PSL Research University Paris FranceTranslational Research Department Institut Curie, PSL Research University Paris FranceTranslational Research Department Institut Curie, PSL Research University Paris FranceTranslational Research Department Institut Curie, PSL Research University Paris FrancePlatform of Investigative Pathology, Department of Pathology Institut Curie Paris FranceTranslational Research Department Institut Curie, PSL Research University Paris FranceTranslational Research Department Institut Curie, PSL Research University Paris FranceTranslational Research Department Institut Curie, PSL Research University Paris FranceTranslational Research Department Institut Curie, PSL Research University Paris FrancePlatform of Investigative Pathology, Department of Pathology Institut Curie Paris FrancePlatform of Investigative Pathology, Department of Pathology Institut Curie Paris FranceInstitute of Plant Sciences Paris‐Saclay (IPS2), UMR 9213, UMR1403, CNRS, INRA Université Paris‐Sud, Université d'Evry, Université Paris‐Diderot, Sorbonne, Paris‐Cité Orsay FranceTranslational Research Department Institut Curie, PSL Research University Paris FranceTranslational Research Department Institut Curie, PSL Research University Paris FranceTranslational Research Department Institut Curie, PSL Research University Paris FranceTranslational Research Department Institut Curie, PSL Research University Paris FranceAbstract TNBC is a highly heterogeneous and aggressive breast cancer subtype associated with high relapse rates, and for which no targeted therapy yet exists. Protein arginine methyltransferase 5 (PRMT5), an enzyme which catalyzes the methylation of arginines on histone and non‐histone proteins, has recently emerged as a putative target for cancer therapy. Potent and specific PRMT5 inhibitors have been developed, but the therapeutic efficacy of PRMT5 targeting in TNBC has not yet been demonstrated. Here, we examine the expression of PRMT5 in a human breast cancer cohort obtained from the Institut Curie, and evaluate the therapeutic potential of pharmacological inhibition of PRMT5 in TNBC. We find that PRMT5 mRNA and protein are expressed at comparable levels in TNBC, luminal breast tumors, and healthy mammary tissues. However, immunohistochemistry analyses reveal that PRMT5 is differentially localized in TNBC compared to other breast cancer subtypes and to normal breast tissues. PRMT5 is heterogeneously expressed in TNBC and high PRMT5 expression correlates with poor prognosis within this breast cancer subtype. Using the small‐molecule inhibitor EPZ015666, we show that PRMT5 inhibition impairs cell proliferation in a subset of TNBC cell lines. PRMT5 inhibition triggers apoptosis, regulates cell cycle progression and decreases mammosphere formation. Furthermore, EPZ015666 administration to a patient‐derived xenograft model of TNBC significantly deters tumor progression. Finally, we reveal potentiation between EGFR and PRMT5 targeting, suggestive of a beneficial combination therapy. Our findings highlight a distinctive subcellular localization of PRMT5 in TNBC, and uphold PRMT5 targeting, alone or in combination, as a relevant treatment strategy for a subset of TNBC.https://doi.org/10.1002/cam4.2114breast cancermolecular biologytargeted therapytranslational research |
| spellingShingle | Mathilde Vinet Samyuktha Suresh Virginie Maire Clarisse Monchecourt Fariba Némati Laetitia Lesage Fabienne Pierre Mengliang Ye Auriane Lescure Amélie Brisson Didier Meseure André Nicolas Guillem Rigaill Elisabetta Marangoni Elaine Del Nery Sergio Roman‐Roman Thierry Dubois Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers Cancer Medicine breast cancer molecular biology targeted therapy translational research |
| title | Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers |
| title_full | Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers |
| title_fullStr | Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers |
| title_full_unstemmed | Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers |
| title_short | Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers |
| title_sort | protein arginine methyltransferase 5 a novel therapeutic target for triple negative breast cancers |
| topic | breast cancer molecular biology targeted therapy translational research |
| url | https://doi.org/10.1002/cam4.2114 |
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