Work with cancer cell lines suggests that HER-2 gene activity contributes strongly to recurrence of prostate cancer through reactivation of androgen receptors, according to an article in the April 15th issue of Cancer Research.

It is well established that in about 25 percent of breast cancers, overexpression of HER-2 drives rapid progression of breast cancer. Herceptin, a monoclonal antibody, was developed to treat these patients by suppressing the activity of epidermal growth factor receptor 2.

"The treatment with the antibody has been a uniform failure in prostate cancer because the gene is not overexpressed in this disease. We need a different approach to attack HER-2 in prostate cancer," said the study's senior author, Dr. Young Whang. "We believe that the driving force for recurrence of prostate cancer is the reactivation of the androgen receptor, which normally requires the presence of androgen, and this reactivation of the androgen receptor underlies tumor progression of prostate cancer despite hormonal therapy. Exactly how this occurs, we're not sure, but our hypothesis is that activation of HER-2 tyrosine kinase leads to activation of the androgen receptor."

In testing their hypothesis, Whang and colleagues inhibited HER-2 activity in two laboratory experiments involving human cancer cells. In the first, they used an artificial antibody to HER-2 delivered directly into the cells via a modified virus. In the second, they used an experimental drug that specifically inhibits HER-2 tyrosine kinase activity. The oral drug lapatinib is currently in an advanced clinical trial involving patients whose breast cancer is driven by HER-2.

In both experiments, tyrosine kinase activity and androgen receptor function were largely eliminated. "We discovered that inhibition of HER-2 strongly inhibits proliferation of prostate cancer cells and the function of androgen receptor," Whang said.

To properly carry out its function, the androgen receptor protein binds specifically to the regulatory DNA sequence of the genes regulated by androgens such as testosterone, he said. "And we have shown that inhibition of HER-2 impairs the androgen receptor function at this step of binding to the DNA sequence of critical genes such as prostate specific antigen."

The implication of this work, he added, is that HER-2 is important and necessary for prostate cancer viability and progression.

"This provides the rationale for initiating a clinical trial of this novel drug inhibiting HER-2, which is being planned for patients within several months," Whang said. "I envision this drug becoming one of several that could be used in combination with other specifically targeted drugs to prolong the lives of prostate cancer patients."