Abstract B67: The DLK1-DIO3 imprinted region regulates long-term proliferation in normal and malignant breast epithelium

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Abstract DNA methylation changes are common in cancers, but their consequences are not fully understood. The DLK1-DIO3 locus, whose transcripts are controlled by the imprinted control region IG-DMR, is hypomethylated in 8% of breast cancer patients. Moreover, breast cancer patients with increased copy number of miR-127, an miR encoded in the DLK1-DIO3 locus, had worse disease-specific survival. IG-DMR reporter mice revealed that the elevated expression of miR-127 in immature normal and malignant mammary epithelial cells is controlled by allele-specific DNA methylation. Aberrant expression of miR-127 led to the de novo acquisition of long-term proliferation by normal and malignant mammary epithelial cells. Mechanistically, miR-127 suppresses translation of SETD8 and subsequent H4K20me1 deposition at LATS2, resulting in an effective activation of the Hippo target genes. Our results demonstrate that the DLK1-DIO3 region epigenetically regulates mammary stem cells, contributing to increased proliferative and tumorigenic capacity partially via regulation of the Hippo signaling pathway. Citation Format: Maider Zabala, Neethan A. Lobo, Jose A. Seoane, Yonatan Stelzer, An V. Luong, Taichi Isobe, Mark A. Zarnegar, Nicholas Watanabe, Sonia Antoñana, Jessica Lam, Dalong Qian, Shaheen S. Sikandar, Angera H. Kuo, Luuk S. Heitink, Yohei Shimono, Ferenc A. Scheeren, Shang Cai, Shigeo Hisamori, Debashis Sahoo, Frederick M. Dirbas, George Somlo, Rudolf Jaenisch, Curtis Christina, Michael F. Clarke. The DLK1-DIO3 imprinted region regulates long-term proliferation in normal and malignant breast epithelium [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B67.