Abstract
PurposeCoactivator-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.MethodsTo 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.ResultsImmunofluorescence 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.ConclusionsThe 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.
Highlights
Breast cancer is a heterogeneous disease and is commonly subcategorized based on the expression of intrinsic genomic markers
The analysis presented here lends new insights into the possible oncogenic role of CARM1ΔE15
This study demonstrates no obvious association of Coactivator-associated arginine methyltransferase 1 (CARM1) isoform expression and clinical correlates in breast cancer
Summary
Breast cancer is a heterogeneous disease and is commonly subcategorized based on the expression of intrinsic genomic markers. The most frequently reported markers are the hormone (estrogen and progesterone) receptors [1] as well as the human epidermal growth factor 2 (HER2/ neu) [2]. Additional genomic markers have been incorporated into multi-gene platforms such as Oncotype DX, MammaPrint, and Prosigna for prediction of recurrence risk and selection of adjuvant therapies [3]. Increasing interest in personalized cancer care [4] driven by genomic profiling highlights the value of investigating novel biomarkers for the characterization and treatment of breast cancer. CARM1 was originally identified as a coactivator for steroid hormone receptors, including the estrogen receptor (ER), and was later shown to transactivate other cancer-relevant transcription factors including NF-κB, p53, and β-catenin via methyltransferase-dependent and-independent pathways [5]. CARM1 knock-out mice die perinatally [10], indicating broad physiological functions in proliferation, differentiation, and development for this coactivator
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