Abstract B164: Identification and validation of PRMT1 as a therapeutic target in breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers (BC) associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In the present study, we found that Protein Arginine Methyltransferase 1 (PRMT1) is overexpressed in TNBC at the mRNA level. At the protein level, PRMT1 was overexpressed in all breast cancer subtypes compared to normal breast tissue. The depletion of PRMT1 using siRNA in BC cell lines triggered apoptosis, reduced cell viability and the ability to form colonies in an anchorage-independent manner. Treatment with Furamidine, a new PRMT1-specific inhibitor, blocked proliferation specifically in BC cells, with no measurable effect in normal breast cells. Furamidine treatment of a TNBC patient-derived xenograft (PDX) model significantly slowed tumor growth. To address the cellular pathways regulated by PRMT1, we identified its protein partners by mass spectrometry and the transcriptomic changes following its depletion in TNBC cell lines. Interestingly, we found that PRMT1 directly activates key oncogenic pathways. Furthermore, we found a synergistic interaction between PRMT1 inhibitors and inhibitors for some of those pathways. Our results show that PRMT1 activity is necessary for breast cancer cell survival and oncogenic pathway activation. Our results point out PRMT1 as an emerging target for the treatment of BC. Citation Format: David C. Silvestre, Amelie Brisson, Bérengère Marty-Prouvost, David Gentien, Damarys Loew, Florent Dingli, Virginie Maire, Fariba Némati, Mengliang Ye, Didier Meseure, André Nicolas, Sergio Roman-Roman, Thierry Dubois. Identification and validation of PRMT1 as a therapeutic target in breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B164.