Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers. (8th April 2019)

• Record Type: Journal Article
• Authors: Vinet, Mathilde; Suresh, Samyuktha; Maire, Virginie; Monchecourt, Clarisse; Némati, Fariba; Lesage, Laetitia; Pierre, Fabienne; Ye, Mengliang; Lescure, Auriane; Brisson, Amélie; Meseure, Didier; Nicolas, André; Rigaill, Guillem; Marangoni, Elisabetta; Del Nery, Elaine; Roman‐Roman, Sergio; Dubois, Thierry
• Is Part Of: Cancer medicine. Volume 8:Number 5(2019:May)
• Page Start: 2414
• Page End: 2428
• Publication Date: 2019-04-08
• Subjects: breast cancer -- molecular biology -- targeted therapy -- translational research; 616.994005
• DOI: 10.1002/cam4.2114
• Languages: English
• ISSNs: 2045-7634

Abstract

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. Abstract : Alternatives to current treatments are direly needed for patients with triple‐negative breast cancers (TNBC). The present study endorses PRMT5 as a novel therapeutic target in TNBC. PRMT5 pharmacological inhibition decreases viability in a subset of TNBC cell lines, mitigates early‐stage tumor progression in vivo, and displays additive/synergistic effects in combination with EGFR inhibition. Importantly, this study shows distinctive PRMT5 subcellular localization in TNBC, underlining the importance of site‐specific PRMT5 activity in the context of breast cancers.