Researchers at the Massachusetts General Hospital Cancer Center (MGH) identified a subgroup of hard-to-treat breast cancers that may be sensitive to the drug cisplatin. They also discovered the molecular basis of this sensitivity, which may help identify patients most likely to benefit from cisplatin treatment.
About two thirds of breast cancers contain receptor molecules for the hormones estrogen or progesterone and can be treated with antiestrogen drugs. About 20–30% of tumors have elevated levels of a growth-promoting protein called HER2. The third major subtype is the 15–20% of breast tumors that have neither estrogen nor progesterone receptors and also do not overexpress HER2.
Since these triple-negative tumors are treatable with neither Herceptin nor antiestrogen drugs, the prognosis for patients with the tumors has been poor. Based on previous reports, the current study was designed to see if triple-negative tumors might be sensitive to cisplatin and to investigate the underlying mechanism.
The team focused on the function of p63, a protein that plays a role in normal breast development and is related to the common tumor suppressor p53. They analyzed tissue samples from triple-negative breast tumors and normal breast tissues for the expression of several forms of p63 and another related protein called p73, known to promote apoptosis.
The researchers found that a significant number of triple-negative tumors overexpress particular forms of p63 and p73, a pattern not seen in other types of breast cancers. Using an RNAi system to inhibit the action of p63, they showed that the protein stimulates tumor growth by interfering with p73’s normal ability to induce cell death. Cisplatin was found to break up the binding of p63 to p73 and reactivate the cell-death process.
"The most important finding was that, if the tumor cells did not express both p63 and p73, the cells were not sensitive to cisplatin," says Leif Ellisen, Ph.D., M.D., assistant professor of Medicine at Harvard Medical School and senior author. "These results suggest that testing p63 and p73 levels in patients’ tumors might help predict whether they would benefit from cisplatin therapy."
Based on the research, a clinical trial to investigate the role of p63/p73 expression in determining cisplatin sensitivity will be led by MGH researchers through the Dana-Farber/Harvard Cancer Center in Boston in the coming weeks.
The results of the study will appear in the May 2007 issue of Journal of Clinical Investigation and is available now online.