Turning off Breast Cancer: New Study Might be the Key

Researchers at the Medical College of Georgia at Georgia Regents University recently announced their discovery that the gene DNMT1 is essential in maintaining breast, or mammary, stem cells, which enable normal rapid growth of the breasts during pregnancy, as well as the cancer stem cells that may enable breast cancer. They've learned that the DNMT1 gene also is highly expressed in the most common types of breast cancer.

Dr. Muthusamy Thangaraju, a biochemist at the university and corresponding author of the study in the journal Nature Communications also found that conversely, the ISL1 gene (a tumor suppressor and natural control mechanism for stem cells) is barely active in the breasts during pregnancy as well as cancer.

"DNMT1 directly regulates ISL1," says Thangaraju. "If the DNMT1 expression is high, this ISL1 gene is low.” This connection was first made when they knocked out DNMT1 in a mouse and noted the increase in ISL1. It was at this juncture they began looking at what happened in human breast cancer cells.

What they discovered is that ISL1 is silent in most human breast cancers and that restoring higher levels to the human breast cancer cells dramatically reduces the stem cell populations and the resulting cell growth and spread that are hallmarks of cancer.

According to Thangaraju, “When they eliminated the DNMT1 gene in a breast-cancer mouse model, the breast won't develop as well, but neither would about 80 percent of breast tumors. The deletion even impacted super-aggressive, triple-negative breast cancer.”

The researchers report that the findings may point toward new therapeutic targets for breast cancer by potentially using blood levels of ISL1 as a way to diagnose early breast cancer. “In fact, they've found that the anti-seizure medication valproic acid, already used in combination with chemotherapy to treat breast cancer, appears to increase ISL1 expression, which may help explain why the drug works for these patients,” says Thangaraju. The scientists are now screening other small molecules that might work as well or better.

According to the American Cancer Society, while the exact reasons remain unclear, there is an increased risk of breast cancer if the first pregnancy occurs after age 30 as well as in women who lose their baby during pregnancy or have an abortion. Women who never have children also are at increased risk, while multiple term pregnancies further decrease the risk.

In five different types of human breast cancer, researchers found high levels of DNMT1 and ISL1 turned off. Even in a laboratory dish, when they put the ISL1 gene back, human breast cancer cells and stem cell activity were much reduced.