PRMT3 regulates the progression of invasive micropapillary carcinoma of the breast

Sep 24, 2026

Uploaded by Oliver

Invasive micropapillary carcinoma (IMPC) is a special histopathological subtype of breast cancer with higher rates of lymphovascular invasion and lymph node metastasis than invasive ductal carcinoma (IDC). Metabolic characteristics and mechanisms driving malignant IMPC behaviors remain unclear. Large-scale targeted metabolomics compared chemotherapy-naïve IMPC (n=25) and IDC (n=26) and integrated mass spectrometry, RNA sequencing, and ChIP-sequencing to define metabolic alterations and molecular drivers.

LanguageEnglish

CategoryHealthcare

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Pages17

Reading Time43 min

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Abstract

Background

Study design and methods

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Received: 11 August 2022 Revised: 22 December 2022 Accepted: 27 December 2022 DOI: 10. 1111/cas.15724 OR I G I NAL ART I C L E PRMT3 regulates the progression of invasive micropapillary carcinoma of the breast Renyong Zhi1,2,3,4,5 | Kailiang Wu1,2,3,4,5 | Jingyue Zhang1,2,3,4,5 | Hanjiao Liu1,2,3,4,5 | Chen Niu1,2,3,4,5 | Shuai Li1,2,3,4,5 | Li Fu1,2,3,4,5 1Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China 2National Clinical Research Center of Cancer, Tianjin, China 3 Key Laboratory of Cancer Prevention and Therapy, Tianjin, China 4Tianjin's Clinical Research Center for Cancer, Tianjin, China 5Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China Correspondence Li Fu and Shuai Li, Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China. Email: [fuli@tmu.edu.cn](fuli@tmu.edu.cn), [shuaili@tmu.edu.cn](shuaili@tmu.edu.cn) Funding information National Natural Science Foundation of China, Grant/Award Number: 31870860, 81872164 and 82173344 Abstract 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 ofarginine 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. Abbreviations: ADMA, Asymmetric NG, NG-dimethylarginine; ASL, Arginine succinate lyase; DTCs, Disseminated tumor cells; EMA/MUC1, Epithelial membrane antigen; ER, Endoplasmic reticulum; EZH2, Enhancer of zeste homolog 2; FOXP1, Forkhead box protein P1; GSSG, Glutathione disulfide; H3K4me3, Histone H3 lysine 4 trimethylation; H3R2me2s, Histone H3 arginine 2 symmetrical dimethylation; H4R3me2a, Histone H4 arginine 3 asymmetric dimethylation; IDC, Invasive ductal carcinoma; IMPC, Invasive micropapillary carcinoma; MLL, Mixed-lineage leukemia; MMA, NG-monomethylarginine; NOS, Nitric oxide synthase; Pol II, RNA polymerase II; PRMT3, Protein arginine methyltransferase 3; SDMA, Symmetric NG, N ′G-dimethylarginine; SET1, SET domain-containing protein 1, histone lysine methyltransferase; TES, Transcription termination site; TSS, Transcription start site; UPR, Unfolded protein response. Renyong Zhi and Kailiang W

FAQs

What distinguishes invasive micropapillary carcinoma (IMPC) from invasive ductal carcinoma (IDC) clinically?

IMPC shows a higher incidence of lymphovascular invasion and lymph node metastasis and has a worse prognosis than IDC.

What was the purpose of the targeted metabolomics analysis in the study?

To identify metabolic alterations between chemotherapy-naïve IMPC and IDC and to uncover potential molecular mechanisms underlying IMPC malignant behaviors.

How is PRMT3 related to IMPC progression and prognosis?

PRMT3 is identified as a critical regulator forming arginine methylation marks, and PRMT3 overexpression is an independent risk factor for poor IMPC prognosis.

Sep 24, 2026

Uploaded by Oliver