Differential CARM1 Isoform Expression in Subcellular Compartments and among Malignant and Benign Breast Tumors

• Published in: PloS one 2015-06, Vol.10 (6), p.e0128143
• Main Authors: Shlensky, David, Mirrielees, Jennifer A, Zhao, Zibo, Wang, Lu, Mahajan, Aparna, Yu, Menggang, Sherer, Nathan M, Wilke, Lee G, Xu, Wei
• Format: Article
• Language: English
• Subjects: Alternative splicing; Antibodies; Arginine; Benign; Benzoquinones - pharmacology; Breast cancer; Breast Neoplasms - diagnosis; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Compartments; Correlation analysis; Cytoplasm; Cytoplasm - drug effects; Cytoplasm - metabolism; Diagnosis, Differential; DNA methylation; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockout Techniques; Gene regulation; Heat shock proteins; Histology; Histones; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Hsp90 protein; Humans; Immunofluorescence; Intracellular Space - drug effects; Intracellular Space - metabolism; Isoenzymes - deficiency; Isoenzymes - genetics; Isoenzymes - metabolism; Isoforms; Laboratories; Lactams, Macrocyclic - pharmacology; Lymph nodes; Medical prognosis; Medicine; Methylation; Molecular chains; Oncology; Prognosis; Protein arginine methyltransferase; Protein Transport - drug effects; Protein-Arginine N-Methyltransferases - deficiency; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Proteins; Proteomics; Public health; RNA; Surgery; Transcription factors; Transferases; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0128143

Coactivator-associated arginine methyltransferase 1 (CARM1) is a coactivator for ERα and cancer-relevant transcription factors, and can methylate diverse cellular targets including histones. CARM1 is expressed in one of two alternative splice isoforms, full-length CARM1 (CARM1FL) and truncated CARM1 (CARM1ΔE15). CARM1FL and CARM1ΔE15 function differently in transcriptional regulation, protein methylation, and mediation of pre-mRNA splicing in cellular models. To investigate the functional roles and the prognosis potential of CARM1 alternative spliced isoforms in breast cancer, we used recently developed antibodies to detect differential CARM1 isoform expression in subcellular compartments and among malignant and benign breast tumors. Immunofluorescence in MDA-MB-231 and BG-1 cell lines demonstrated that CARM1ΔE15 is the dominant isoform expressed in the cytoplasm, and CARM1FL is more nuclear localized. CARM1ΔE15 was found to be more sensitive to Hsp90 inhibition than CARM1FL, indicating that the truncated isoform may be the oncogenic form. Clinical cancer samples did not have significantly higher expression of CARM1FL or CARM1ΔE15 than benign breast samples at the level of mRNA or histology. Furthermore neither CARM1FL nor CARM1ΔE15 expression correlated with breast cancer molecular subtypes, tumor size, or lymph node involvement. The analysis presented here lends new insights into the possible oncogenic role of CARM1ΔE15. This study also demonstrates no obvious association of CARM1 isoform expression and clinical correlates in breast cancer. Recent studies, however, have shown that CARM1 expression correlates with poor prognosis, indicating a need for further studies of both CARM1 isoforms in a large cohort of breast cancer specimens.