Gene associated with breast cancer may play major role in prostate cancer recurrence

04/20/05

CHAPEL HILL -- A gene associated with breast cancer also may play a major role in the recurrence of prostate cancer, according to new research from the University of North Carolina at Chapel Hill School of Medicine and UNC Lineberger Comprehensive Cancer Center.

The most common cancer in men, prostate cancer can be effectively treated with surgery or radiation when detected early. But advanced prostate cancer is usually treated by drugs or surgery aimed at reducing the level of testosterone and other male hormones, or androgens, that stimulate cancer cell growth. While the disease usually regresses after such treatment, prostate cancer invariably comes back, although it's not clear why it recurs and progresses.

The UNC study, published April 15 in the journal Cancer Research, indicates that the gene HER-2 is a key culprit in prostate cancer recurrence. The findings also suggest a new treatment strategy for targeting HER-2 in patients with advanced prostate cancer.

HER-2 refers to human epidermal growth factor receptor 2. The gene helps control how cells grow, divide and repair themselves, and directs the production of a special protein called HER-2 tyrosine kinase. This protein acts as receptors on the cell membrane, and when activated by external hormones, it promotes cell growth and division.

In about one in four breast cancers, a genetic mutation creates too many HER-2 receptors. This helps spur rapid cancer cell growth. While treatment with the antibody drug Herceptin can be effective in slowing breast cancer growth, this is not the case in prostate cancer, researchers said.

"The treatment with the antibody has been a uniform failure in prostate cancer because the gene is not over-expressed in this disease. We need a different approach to attack HER-2 in prostate cancer," said the study's senior author, Dr. Young Whang. He is an assistant professor of medicine and medical oncologist at UNC and a member of UNC Lineberger.

"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 his co-authors 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 (GlaxoSmithKline) 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 derailed.

"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."

UNC co-authors with Whang include postdoctoral researchers Drs. Yuanbo Liu and Samarpan Majumder; Wesley McCall, research technician; Dr. Carolyn Sartor, assistant professor of radiation oncology; Dr. James Mohler, professor of surgery; and Dr. Shelton Earp, director, UNC Lineberger. Dr. Christopher Gregory, former UNC assistant professor of pathology and another co-author, is now with Voyager Pharmaceutical Corp. in Raleigh.

Source: Eurekalert & others

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