TAMOXIFEN SENSITIVITY CAN BE RESTORED

Tamoxifen Sensitivity Can Be Restored in Breast Cancer Cells

NEW YORK (Reuters Health) Feb 27 - Restoration of Wnt-5a signaling in breast cancer cells negative for estrogen receptor alpha (ER-alpha) upregulates expression of the receptor, making the cells susceptible to tamoxifen, investigators report in the February 23 early online edition of the Proceedings of the National Academy of Sciences.

"This novel approach of reconstituting ER-alpha expression... to render tumors responsive to current endocrine treatments could be of significant importance to future clinical management of breast cancer," the researchers conclude.

Dr. Caroline E. Ford and associates at Lund University in Malmo, Sweden, explain that Wnt-5a is a cell surface receptor ligand that increases adhesion and reduces migration of epithelial cells. Previous research has indicated that loss of Wnt-5a and ER-alpha expression tend to occur in tandem.

The researchers theorized that Wnt-5a regulates ER-alpha levels, and that restoring Wnt-5a signaling would reestablish ER-alpha positivity.

To test their theory, they treated several ER-alpha-negative breast cancer cell lines with recombinant Wnt-5a, which did restore mRNA and protein expression of the receptor.

After Wnt-5a stimulation, treatment of the cultured cells with the selective estrogen receptor modulator tamoxifen increased apoptosis and cell growth inhibition.

They replicated their findings in the cultured cells using a small-molecule Wnt-5a-derived hexapeptide (Foxy-5).

They also conducted an in vivo study, in which mice were inoculated with rapidly metastatic, ER-alpha negative breast cancer cells into their mammary fat pads. Treatment with Foxy-5 every 4th day for 25 days significantly upregulated ER-alpha expression compared with control treatment.

Because of its smaller size and binding characteristics that would enhance its distribution in the body, Dr. Ford's team predicts that a molecule such as Foxy-5 will have greater therapeutic potential than recombinant Wnt-5a.

They conclude: "Concordant treatment with a Wnt-5a-mimicking hexapeptide and currently available ER-alpha modulators may represent a novel and beneficial treatment strategy for breast cancer patients with ER-alpha-negative tumors."