Expression, Localization and Prognosis Association of MEP50 in Breast Cancer

Samyuktha Suresh; Mathilde Vinet; Rayan Dakroub; Laetitia Lesage; Mengliang Ye; Hussein Fayyad-Kazan; André Nicolas; Didier Meseure; Thierry Dubois

doi:10.3390/cancers14194766

Expression, Localization and Prognosis Association of MEP50 in Breast Cancer

Cancers (Basel). 2022 Sep 29;14(19):4766. doi: 10.3390/cancers14194766.

Authors

Samyuktha Suresh¹, Mathilde Vinet¹, Rayan Dakroub^{1

2}, Laetitia Lesage³, Mengliang Ye¹, Hussein Fayyad-Kazan², André Nicolas³, Didier Meseure³, Thierry Dubois¹

Affiliations

¹ Breast Cancer Biology Group, Translational Research Department, Institut Curie-PSL Research University, 75005 Paris, France.
² Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath 1003, Lebanon.
³ Platform of Experimental Pathology, Department of Diagnostic and Theranostic Medicine, Institut Curie-Hospital, 75005 Paris, France.

Abstract

Breast cancer is composed of distinct subgroups, triple-negative breast cancer (TNBC), human epidermal growth factor receptor-2 (HER2), luminal A, and luminal B, which are associated with different prognosis. MEP50 is the main partner of the arginine methyltransferase PRMT5 required for its enzymatic activity. Here, we examined MEP50 expression in the different breast cancer subgroups from the transcriptomic data obtained on human breast cancer samples and on normal breast tissues in two cohorts (Curie, n = 141; The Cancer Genome Atlas-TCGA, n = 788). We observed higher levels of MEP50 mRNA in TNBC (Curie, n = 41; TCGA, n = 106) compared to the other breast cancer subgroups and normal breast tissues. Using an online KM-plotter database, which allows survival analyses in a larger number of breast cancer patients, we found that high MEP50 mRNA levels were associated with a more favorable recurrence-free survival (RFS) in TNBC (n = 953, p = 1.2 × 10^-4) and luminal B (n = 1353, p = 0.013) tumors, whereas high PRMT5 mRNA levels were associated with worse RFS in these two subgroups (TNBC: n = 442, p = 1.0 × 10^-⁴; luminal B: n = 566, p = 6.8 × 10^-3). We next determined the expression and the subcellular localization of MEP50 protein by immunohistochemistry (IHC) in our Curie cohort of breast cancer (n = 94) and normal tissues (n = 7) using a validated MEP50 antibody. MEP50 was more expressed in breast tumors compared to normal breast tissues (p = 0.02). MEP50 was more localized to the cytosol in breast cancer cells compared to normal breast tissue (p = 4 × 10^-4), and was more found at the plasma membrane in normal tissues compared to breast tumors (p = 0.01). We also evaluated PRMT5 activity by IHC in our Curie cohort using a validated antibody (H4R3me2s) detecting histone H4 symmetrically dimethylated on Arg3. High levels of H4R3me2s were found in normal breast tissues, whereas the lowest levels of H4R3me2s were observed in TNBC and HER2 breast cancer subgroups. Altogether, our study reports the expression of the PRMT5 cofactor (MEP50) and substrate (H4R3me2s) in breast cancer and highlights the association of PRMT5 and MEP50 mRNA with prognosis in luminal B and TNBC breast cancer subgroups and certain TNBC subtypes.

Keywords: H4R3me2s; MEP50; PRMT5; TNBC; breast cancer; epigenetics; prognosis; recurrence-free survival; triple-negative breast cancer.

Grants and funding

This work was supported by the Institut Curie and the Institut de Recherches Servier. R.D. was financed by the French Embassy and the Lebanese University (Safar Volet 1). M.V. and S.S. were funded by the European Union’s Horizon 2020 Research and Innovation Programme (Marie Skłodowska-Curie grant agreement No 666003).