Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients

A protein that activates estrogen receptors in breast cancer may play a role in resistance to therapeutic effects of anti-estrogen tamoxifen treatment, according to a study in the Journal of the National Cancer Institute.

Pak 1 is a member of a family of proteins involved in many cell functions, such as gene expression, cell movement, and cell death. Previous studies have suggested that the presence of this protein may lead to more invasive breast cancer.

Goran Landberg, M.D., Lund University in Malmv, Sweden, and colleagues examined Pak1 expression in 403 premenopausal women with breast cancer. The women participated in a clinical trial where they were randomly assigned to receive tamoxifen therapy or no treatment. The authors examined whether tumor levels of Pak1 were associated with the women's chances of breast cancer recurrence and the effects of tamoxifen therapy.

The authors found that increased Pak1 expression was associated with increased resistance to tamoxifen therapy for women with estrogen receptor positive breast cancer. Patients with ER-positive tumors and low levels of Pak1 had longer survival without tumor recurrence than patients who did not receive treatment. Overexpression of certain types of Pak1 was associated with decreased response to tamoxifen therapy.

The authors write, "Overall, our observations suggest that Pak1 activation and nuclear localization contribute to the reduced tamoxifen sensitivity that has been observed in some breast tumor cells. Therapies that target Pak1 expression or activity may therefore represent a strategy to increase the endocrine treatment response in breast cancer."

In an accompanying editorial, V. Craig Jordan, Ph.D., D.Sc., of Fox Chase Cancer Center in Philadelphia, discusses what is known about resistance to tamoxifen therapy. He writes, "The clinical correlations reported by Holm et al. indicate that packing tumor cell nuclei with Pak can perturb tamoxifen's action. The tumor, once "Paked up", has no alternative but to grow."