DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis

• DOI: 10.1038/ncomms7910
• Publication Date: 2015-04-24T11:55:34Z
• Authors: Rajneesh Pathania; Sabarish Ramachan...; Selvakumar Elangovan; Ravi Padia; Pengyi Yang; Senthilkumar Cinghu; Rajalakshmi Veera...; Pachiappan Arjunan; Jaya P. Gnana-Pra...; Fulzele Sadanand; Lirong Pei; Chang-Sheng Chang; Jeong-Hyeon Choi; Huidong Shi; Santhakumar Manic...; Puttur D Prasad; Suash Sharma; Vadivel Ganapathy; Raja Jothi; Muthusamy Thangaraju
• Keywords: DNA (Cytosine-5-)-Methyltransferase 1; 0303 health sciences; Carcinogenesis; Stem Cells; Blotting, Western; LIM-Homeodomain Proteins; Down-Regulation; Mammary Neoplasms, Experimental; Breast Neoplasms; DNA Methylation; Article; Cell Line; 3. Good health; Mice; 03 medical and health sciences; Mammary Glands, Animal; Microscopy, Fluorescence; Cell Line, Tumor; MCF-7 Cells; Neoplastic Stem Cells; Animals; Humans; Female; DNA (Cytosine-5-)-Methyltransferases

Mammary stem/progenitor cells (MaSCs) maintain self-renewal of the mammary epithelium during puberty and pregnancy. DNA methylation provides a potential epigenetic mechanism for maintaining cellular memory during self-renewal. Although DNA methyltransferases (DNMTs) are dispensable for embryonic stem cell maintenance, their role in maintaining MaSCs and cancer stem cells (CSCs) in constantly replenishing mammary epithelium is unclear. Here we show that DNMT1 is indispensable for MaSC maintenance. Furthermore, we find that DNMT1 expression is elevated in mammary tumours, and mammary gland-specific DNMT1 deletion protects mice from mammary tumorigenesis by limiting the CSC pool. Through genome-scale methylation studies, we identify ISL1 as a direct DNMT1 target, hypermethylated and downregulated in mammary tumours and CSCs. DNMT inhibition or ISL1 expression in breast cancer cells limits CSC population. Altogether, our studies uncover an essential role for DNMT1 in MaSC and CSC maintenance and identify DNMT1-ISL1 axis as a potential therapeutic target for breast cancer treatment.