Protein holds possible clues to tamoxifen resistance in breast cancer

Resistance to tamoxifen in women taking the drug for estrogen receptor (ER)-positive breast tumors may be linked to low levels of a protein called Rho GDI-alpha, a new study from Baylor College of Medicine suggests.

The research was published online March 30 in the Journal of the National Cancer Institute.

Researchers compared 4 primary ER-positive tumors from women who did not have a recurrence while taking tamoxifen with 5 tumors from women whose cancer metastasized while they were on the drug. They found low levels of Rho GDI-alpha in the women with tamoxifen-resistant metastatic disease. The researchers validated the association between levels of Rho GDI-alpha and tamoxifen resistance in laboratory cells, human tumors implanted in mice, and genetic data from 250 women with tamoxifen-treated ER-positive breast tumors.

Investigators also found that when levels of Rho GDI-alpha decreased, levels of another protein, MTA2, rose significantly and that, taken together, levels of the 2 proteins predicted recurrence. “These are the first data suggesting a tight, clinically important connection between the 2 pathways, Rho GDI-alpha and MTA2,” the authors write. “Our data also suggest a possible mechanism in which the loss of Rho GDI-alpha function promotes distant progression of breast tumors by triggering downstream molecules, such as MTA2, with metastasis-promoting activities.”

Other studies have found the 2 proteins to be associated with breast cancer in various ways, but not all the findings are consistent with the results of the new study, according to an accompanying editorial by Matthew J. Ellis, PhD, and Brian A. Van Time, MD, of Washington University in St. Louis. For this reason, “the status of Rho GDI-alpha as a marker of tamoxifen resistance is unclear,” they write.