METTL3-dependent m6A RNA methylation suppresses aberrant mammary epithelial differentiation and neoplastic transformation

Yihao Li, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Xintao Qiu, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Zachary Sandusky, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Kaitlin Tagliaferri, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115.
Rong Li, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Xin Yang, Department of Molecular, Cell, and Cancer Biology, UMass Chan Medical School, Worcester, MA 01605.
Tao Zhang, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Shimeng Liu, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Pengze Yan, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Feng Lu, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Marcus Jones, Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115.
Tengfei Xiao, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Wei Li, Center for Genetic Medicine Research, Children's National Hospital, Washington, DC 20010.
Seth Goldman, Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115.
Jie Cui, Shanghai Sci-Tech Inno Center for Infection and Immunity, National Medical Center for Infectious Diseases, Huashan Hospital, Institute of Infection and Health, Fudan University, Shanghai 200433, China.
Kornelia Polyak, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
X Shirley Liu, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115.
Henry W. Long, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Richard I. Gregory, Department of Molecular, Cell, and Cancer Biology, UMass Chan Medical School, Worcester, MA 01605.
Karen Adelman, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115.
Jennifer M. Rosenbluth, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Myles Brown, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.

Document Type

Journal Article

Publication Date

11-18-2025

Journal

Proceedings of the National Academy of Sciences of the United States of America

Volume

122

Issue

46

DOI

10.1073/pnas.2514643122

Keywords

RNA methylation; breast cancer; epitranscriptomics; mammary development; transposable elements

Abstract

The mechanisms underlying sustained proliferation and aberrant cellular plasticity that drive early breast tumorigenesis remain unclear. Using CRISPR knockout (KO) screens, we systematically characterized the regulators of cellular fitness in the normal mammary epithelium. We found that loss of METTL3 stimulates mammary epithelial proliferation and reprograms gene expression in an m6A methyltransferase-dependent manner. Single-cell analysis in normal breast organoids revealed that METTL3 ablation causes disruption of the mammary cellular hierarchy through increased aberrant luminal differentiation. Mechanistically, METTL3 loss reduces RNA m6A modification of transcribed transposable elements leading to their increased expression and upregulation of interferon-STAT signaling. This inflammatory response leads to cross talk between STAT and GATA3 transcription factors, resulting in transcriptional activation of luminal genes in the mammary epithelium. These findings identify a cell-intrinsic epigenetic loop contributing to mammary epithelial differentiation and highlight a potential role of loss of METTL3-dependent m6A modification during neoplastic transformation.

Department

Pediatrics

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