The estrogen inhibitor tamoxifen can prevent breast cancer from coming back in treated women whose tumors grow in the presence of the hormone. Unfortunately, tamoxifen’s anti-tumor effect wanes in about half of these women, and now researchers from the Lester and Sue Smith Breast Center at Baylor College of Medicine think they know why.

Low levels or loss of the protein Rho guanine disassociation inhibitor alpha or Rho GDI alpha can cause tumors to resist the effects of treatment with tamoxifen and similar drugs and can lead to breast cancer spread (called metastasis), said Dr. Suzanne Fuqua, professor in the Smith Breast Center and lead author of the report that published online today in the Journal of the National Cancer Institute.

"We have effective therapies like tamoxifen for estrogen receptor positive breast cancer, but in some tumors, resistance to this therapy eventually develops and the cancer comes back and metastasizes or spreads,"said Fuqua, who is also a professor of medicine and molecular and cellular biology at BCM. "This is a major clinical problem. It’s the metastasis that kills the patient."

Why do tumors become resistant therapy?

In this type of cancer, estrogen causes the breast cancer cells to grow. Tamoxifen works by binding to the estrogen receptor and preventing the hormone from entering the cancer cell and encouraging its growth.

In this study, Fuqua and colleagues set out to find what genetic changes might cause some tumors to become resistant to anti-estrogen therapy and why cancers spread.

The team conducted a microarray tumor analysis (an analysis of all the genes in the tumor using a gene chip), comparing tumors from patients who received tamoxifen and whose tumors did not recur to patients who developed resistance to tamoxifen and whose cancer progressed.

In their analysis, the researchers identified that there were low levels of Rho GDI alpha in the tamoxifen-resistant group.

Importance of Rho signaling pathway

"We know some members of the Rho protein family are involved in cell survival, growth and metastasis,"said Fuqua. "The Rho signaling pathway is an integral part of these processes."

Rho GDI alpha works as a negative regulator of the Rho signaling pathway, blocking that signal for metastasis or cancer spread, she said. "Without this protein’s regulation, we think the door is open for resistance (to tamoxifen) and metastasis."

Confirming the Rho GDI hypothesis

To test this hypothesis, Fuqua and team conducted further studies in animals.

"We tested animals with both high and no levels of Rho GDI alpha,"said Fuqua. "We once again observed both the resistance and metastasis."

Treatments available to target pathway

"The good news is that there are treatments currently available that target this pathway,"said Fuqua.

"And this study represents the first model researchers can use to study estrogen receptor positive breast cancer that has metastasized."

With this model, researchers can test new drugs for their effects not only on treatment response, but also effects on stopping metastasis, Fuqua said.

Other BCM researchers involved in this study include Dr. Susan Hilsenbeck, professor in the Smith Breast Center; Dr. Gary Chamness, professor in the Smith Breast Center; Lauren Brusco; Guowei Gu; Jennifer Selever; Amanda Beyer; Kyle Covington; Anna Tsimelzon and Tao Wang. Also involved were Dr. Ines Barone and Dr. Sebastiano Ando from the University of Calabria, Arcavacata di Rende, Cosenza, Italy.

The study was supported by the National Institutes of Health and the Cancer Prevention and Research Institute of Texas.

The Lester and Sue Smith Breast Center is a part of the NCI-designated Dan L Duncan Cancer Center at BCM.