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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. The Thangaraju laboratory has recently shown that DNMT1 is indispensable for MaSC maintenance. Furthermore, they found that DNMT1 expression is elevated in mammary tumors, and mammary gland-specific DNMT1deletion protects mice from mammary tumorigenesis by limiting the CSC pool. Through genome-scale methylation studies, they identified ISL1 as a direct DNMT1 target, hypermethylated and downregulated in mammary tumors and CSCs. DNMT inhibition or ISL1 expression in breast cancer cells limits CSC population. Altogether, these studies uncover an essential role for DNMT1 in MaSC and CSC maintenance and identify the DNMT1-ISL1 axis as a potential therapeutic target for breast cancer treatment. This laboratory also identified a small molecule inhibitor that inhibits DNMT1 along with inhibition of histone methyltransferases (HMTs), like DOT1L, MLL1, NSD1, and SETD2. In addition, this small molecule inhibitor prevents breast cancer by blocking breast cancer stem cells, specifically basal myoepithelial stem cells. They are evaluating the therapeutic potential of this drug for breast cancer prevention and treatment.

The Thangaraju laboratory is also evaluating the role of the G-protein coupled receptor 109A (GPR109A), Niacin and Butyrate receptor, and membrane transporter SLC5A8, a butyrate receptor, in mammary gland remodeling and their relevance to breast cancer prevention and treatment. In addition, this laboratory is evaluating the functional implication of silent information regulator 1 (SIRT1) in the regulation of mammary gland development and its role in mammary tumor growth and progression. Some of the important projects ongoing and/or of interest in the group are:

• Functional relevance of mammary gland remodeling in prevention and treatment of breast cancer
• Role of epigenetic regulators in mammary stem/progenitor and cancer stem cells
• Identification of small molecule inhibitors to inhibit DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs) and its relevance to regulation of breast cancer stem cells.