In a recent study published in the Proceedings of the National Academy of Sciences, a team of researchers from the Johns Hopkins Kimmel Cancer Center found a gene, MACROD2, which may account for tamoxifen resistance in certain breast cancer patitents.
The research team, led by Ben Ho Park, M.D., Ph.D., an associate professor of oncology in the Kimmel Cancer Center’s Breast Cancer Program, found that MACROD2 could also be of use during the genetic screening process for particularly aggressive forms of breast cancer, and in the future it could also be targeted for therapy.
ER+ breast cancer cells produce estrogen receptors that bind and respond to estrogen. Tamoxifen can stop this process, however some cancers can acquire resistance to this drug. The team found that MACROD2 codes for a signaling pathway involved in tamoxifen resistance, allowing cancer cells to proliferate instead of regressing.
Upon overexpressing the gene in breast cancer cells, researchers found these become more resistant to tamoxifen. However, after silencing the gene with an RNA molecule, breast cancer cells partially regained sensitivity to tamoxifen, revealing that there are other mechanistic elements behind this reaction.
The team analyzed two databases, The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium study, and found that patients who had higher levels of MACROD2 in their primary tumors, had worse survival outcomes than patients who did not express this gene.
Furthermore, MACROD2 overexpression was associated with more metastasis found in patients who had resistance to tamoxifen, suggesting that resistance was probably acquired throughout time, during treatment.
The few cells in breast cancer patients who overexpress MACROD2 become resistant to treatment. These cells have a survival advantage allowing them to proliferate and grow, resulting in disease progression and metastasis. Dr. Park explained in a news release, “The resultant cells—or the vast majority of them—are now all overexpressing MACROD2, and are the cells that are aggressive and will cause trouble”.
However, other factors are involved in this acquired resistance, and the authors emphasize that nothing in their work suggests tamoxifen use should be avoided.