The hormone treatment tamoxifen is used to treat estrogen receptor-alpha (ER) positive breast cancers and to prevent their recurrence, but the lack of response in some tumors is an unmet medical need. Through data mining, researchers have made a link between the resistance and overexpression of a gene, MACROD2, which might help improve cancer monitoring and treatment. The results have been published in Proceedings of the National Academy of Sciences.
Tamoxifen acts by blocking the estrogen receptor, and while a subset of patients does not respond, few of the molecular mediators behind this resistance have been uncovered. The team, at Johns Hopkins Kimmel Cancer Center, mined through the genetic records of thousands of breast cancer patients from The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium study. They found that patients who overexpress the MACROD2 gene had significantly worse survival rates than those who did not, and that overexpression was present in the majority of metastases in patients with tamoxifen-resistant tumors and in tumor cells that had spread from their original site in the breast. This suggests that tamoxifen resistance caused by the gene might be a process that develops over time as women take the drug.
The research has been supported on the lab bench, where silencing MACROD2 with RNA partially restored cells’ sensitivity to tamoxifen.
“The gene… might also be useful in screening for some aggressive forms of breast cancers, and, someday, offering a new target for therapy,” says Ben Ho Park, of the Kimmel Cancer Center’s Breast Cancer Program.