PRMT3 regulates the progression of invasive micropapillary carcinoma of the breast

• Published in: Cancer science 2023-05, Vol.114 (5), p.1912-1928
• Main Authors: Zhi, Renyong, Wu, Kailiang, Zhang, Jingyue, Liu, Hanjiao, Niu, Chen, Li, Shuai, Fu, Li
• Format: Article
• Language: English
• Subjects: Antibodies; Arginine; arginine methylation; Biomarkers; Breast - pathology; Breast cancer; Breast Neoplasms - pathology; Carcinoma, Ductal, Breast - metabolism; Carcinoma, Papillary - metabolism; Cell proliferation; Chemotherapy; Endoplasmic reticulum; Enzymes; Female; Histone H4; Histones; Humans; Invasiveness; Lymph nodes; Mass spectrometry; Mass spectroscopy; Metabolism; Metabolites; Metabolomics; Metastases; Metastasis; Methylation; Molecular modelling; Original; Patients; proliferation; Protein arginine methyltransferase; protein arginine methyltransferases; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Proteins; Risk factors; RNA polymerase; Scientific imaging; Signal transduction
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15724

Invasive micropapillary carcinoma (IMPC) is a special histopathological subtype of breast cancer. Clinically, IMPC exhibits a higher incidence of lymphovascular invasion and lymph node metastasis compared with that of invasive ductal carcinoma (IDC), the most common type. However, the metabolic characteristics and related mechanisms underlying malignant IMPC biological behaviors are unknown. We performed large‐scale targeted metabolomics analysis on resected tumors obtained from chemotherapy‐naïve IMPC (n = 25) and IDC (n = 26) patients to investigate metabolic alterations, and we integrated mass spectrometry analysis, RNA sequencing, and ChIP‐sequencing data to elucidate the potential molecular mechanisms. The metabolomics revealed distinct metabolic profiles between IMPC and IDC. For IMPC patients, the metabolomic profile was characterized by significantly high levels of arginine methylation marks, and protein arginine methyltransferase 3 (PRMT3) was identified as a critical regulator that catalyzed the formation of these arginine methylation marks. Notably, overexpression of PRMT3 was an independent risk factor for poor IMPC prognosis. Furthermore, we demonstrated that PRMT3 was a key regulator of breast cancer cell proliferation and metastasis both in vitro and in vivo, and treatment with a preclinical PRMT3 inhibitor decreased the xenograft tumorigenic capacity. Mechanistically, PRMT3 regulated the endoplasmic reticulum (ER) stress signaling pathway by facilitating histone H4 arginine 3 asymmetric dimethylation (H4R3me2a), which may endow breast cancer cells with great proliferative and metastatic capacity. Our findings highlight PRMT3 importance in regulating the malignant biological behavior of IMPC and suggest that small‐molecule inhibitors of PRMT3 activity might be promising breast cancer treatments. The elevated expression of PRMT3 promotes H4R3me2a, which might increase H3K4me3 and Pol II localization to the promoter‐proximal regions of endoplasmic reticulum stress‐related genes to facilitate transcription.