Johns Hopkins scientists link gene to tamoxifen-resistant breast cancers

Nov. 26, 2014

Researchers from the Johns Hopkins Kimmel Cancer Center have identified a gene whose presence may explain why some breast cancers are resistant to tamoxifen, the drug used to treat estrogen receptor-positive breast cancers. The findings were published recently in the Proceedings of the National Academy of Sciences.

Cells in this type of breast cancer produce protein receptors in their nuclei which bind to and grow in response to the hormone estrogen. Tamoxifen generally blocks the binding process of the estrogen-receptor, but some estrogen receptor-positive cancers are resistant or become resistant to tamoxifen therapy, finding ways to elude its effects. MACROD2 appears to code for a biological path to tamoxifen resistance by diverting the drug from its customary blocking process to a different way of latching onto breast cancer cell receptors, causing cancer cell growth rather than suppression. Specifically, the team’s experiments found that when the gene is over-expressed in breast cancer cells, producing more of its protein product than normal, the cells become resistant to tamoxifen.

To conduct the study, the scientists examined two well-known databases of breast cancer patients’ genetic information, The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium study. Patients who had MACROD2 over-expressed in primary breast cancers at the original breast cancer site had significantly worse survival rates than those who did not, according to an analysis of the patient databases. With this in mind, the Johns Hopkins scientists suggest that clinicians may be able to look at MACROD2 activity to help them identify aggressive breast cancers at early stages of growth.

The team’s analysis also found that MACROD2 over-expression 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. The finding suggests that tamoxifen resistance caused by the gene might be a process that develops over time as women take the drug. Read the study abstract.

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