New therapeutic target discovered for breast cancer

Published in Nature Communications, Dr. Muthusamy Thangaraju led a collaborative study that included Cancer Center researchers Drs. Chang-Sheng Chang, Jeong-Hyeon Choi, Huidong Shi, Santhakumar Manicassamy, and Puttur Prasad, investigating DNA methyltransferases and mammary stem/progenitor cells. They demonstrated that mammary tumors and cancer stem cells (CSCs) have increased DNMT1 expression and that deleting DNMT1 specifically from the mammary gland prevented mammary gland tumorigenesis. Subsequent genome-scale methylation studies revealed that this protection from tumorigenesis occurred due to elevated levels of the DNMT1 target ISL1; in mammary tumors, ISL1 is hypermethylated/downregulated. This work provides several key pieces of data: They present the first in vivo evidence that DNMT1 is essential for mammary stem cell and CSC maintenance, as well as for mammary tumor formation; they also suggest that ISL1 hypermethylation status is a biomarker for early stage breast cancer and postulate the use of DNMT1 inhibitors as a strategy to reduce tumor load, decrease CSC numbers, and target disease recurrence.