Mouse Models of Overexpression Reveal Distinct Oncogenic Roles for Different Type I Protein Arginine Methyltransferases

Abstract

Protein arginine methyltransferases (PRMTs) are generally not mutated in diseased states, but they are overexpressed in a number of cancers, including breast cancer. To address the possible roles of PRMT overexpression in mammary gland tumorigenesis, we generated Cre-activated PRMT1, CARM1 and PRMT6 overexpression mouse models. These three enzymes are the primary Type I PRMTs and are responsible for the majority of the asymmetric arginine methylation deposited in the cells. Using either a keratin 5-Cre recombinase (K5-Cre) cross or an MMTV-NIC mouse, we investigated the impact of PRMT overexpression alone or in the context of a HER2-driven model of breast cancer, respectively. The overexpression of all three PRMTs induces hyper-branching of the mammary glands and increased Ki-67 staining. When combined with the MMTV-NIC model, these in vivo experiments provided the first genetic evidence implicating elevated levels of these three PRMT in mammary gland tumorigenesis, albeit with variable degrees of tumor promotion and latency. In addition, these mouse models provided valuable tools for exploring the biological roles and molecular mechanisms of PRMT overexpression in the mammary gland. For example, transcriptome analysis of purified mammary epithelial cells isolated from bigenic NIC-PRMT1Tg and NIC-PRMT6Tg mice revealed a deregulated PI3K/AKT pathway. In the future, these PRMTTg lines can be leveraged to investigate the roles of arginine methylation in other tissues and tumor model systems using different tissue-specific Cre crosses, and they can also be used for testing the in vivo efficacy of small molecule inhibitors that target these PRMT.

PRMT6 Promotes Lung Tumor Progression via the Alternate Activation of Tumor-Associated Macrophages

“…1C and D). Consistent with our observations, a recent report demonstrated hyperbranching of the mammary glands and increased ki-67 staining in the breast epithelium of PRMT6 GOF transgenic mice (25).…”

Arginine methylation‐dependent LSD1 stability promotes invasion and metastasis of breast cancer

“…Notably, recent studies indicate that the role of CARM1 is complex and context‐dependent in cancer development, which functions both as a tumor‐suppressor and as a tumor‐promoting protein . Importantly, in vivo studies have shown the oncogenic activities of CARM1 in breast cancer ; nevertheless, the molecular basis of this complexity in CARM1's action remained largely unexplored prior to this study. Our study demonstrates that CARM1 and LSD1 are highly expressed in human breast cancerous tissues compared with the non‐cancerous tissues (Fig EV2), and CARM1 expression is elevated in malignant breast cancer (Fig D) and is positively correlated with LSD1 R838me2a and LSD1 levels (Fig F and G), suggesting a tumor‐promoting role of this protein in breast carcinoma.…”

PRMT1-mediated methylation of the Large Drosha Complex regulates microRNA biogenesis

“…Interestingly, PRMTs are de-regulated in several types of cancer [39] and in particular PRMT1 overexpression was shown to positively correlate with tumor progression [84,85]. Also, a recent study has showed that the overexpression of type-I PRMTs, including PRMT1, promotes mammary gland tumorigenesis in mice [86]. Similarly, microRNA expression is often altered in cancer, where these molecules can display either oncogenic or tumour-suppressive functions [87][88][89].…”