Adding Two Inhibitors Enhances Effectiveness of Tamoxifen in ER-positive Breast Cancer
Combining 2 existing chemotherapy drugs reduced the numbers of cancer stem cells and improved survival in a mouse model. Cancer stem cells are thought to enable the spread and recurrence of cancer.1
Neither drug was effective on its own, but together they were effective. The drugs are 5-azacytidine, which inhibits DNA methyltransferase 1 (DNMT1), and butyrate, which inhibits histone deacetylase. Breast cancer expresses much higher levels of DNMT1 than a healthy adult breast. Butyrate, which is present at high levels in breast milk, blocks excessive levels of molecules that cancer uses to support its growth.
The risk of recurrence of breast cancer is most concerning for patients whose breast cancer was diagnosed in the advanced stage and those with HER2-positive breast cancer, which means they have a growth factor receptor that further aids cancer growth. Overall, approximately 20% to 45% of breast cancer recurs, and this can happen even decades after the initial diagnosis.
"Most current chemotherapy does not kill the stem cells, which are the cells of origin, only the tumor mass," said Muthusamy Thangaraju, PhD, an associate professor in the Department of Biochemistry and Molecular Biology at the Medical College of Georgia and Georgia Cancer Center at Augusta University.
"This combination might need to be considered for all breast cancer patients because their common denominator is cancer stem cells," said Thangaraju.
Currently, these 2 drugs are used together to boost the effectiveness of tamoxifen, commonly used to treat estrogen-receptor positive breast cancer. Approximately 70% of breast cancers are estrogen-receptor positive. Adding these 2 drugs to tamoxifen reduces the rate of recurrence.
5-azacytidine and butyrate directly affect the ability of stem cells to spread as myoepithelial cells and to alter gene expression to promote growth. The researchers used a human breast cancer cell line and a mouse model to test their hypotheses.
The work was funded by the National Cancer Institute and the Department of Defense.
1. Pathania R, Ramachandran S, Mariappan G, et al. Combined inhibition of DNMT and HDAC blocks the tumorigenicity of cancer stem-like cells and attenuates mammary tumor growth [published online ahead of print April 5, 2016]. Cancer Res. doi:10.1158/0008-5472.CAN-15-2249.