Researchers in Ireland may have found a promising treatment for patients with triple-negative breast cancer, the most aggressive form of breast cancer.
Their study, “Mutant p53: a novel target for the treatment of patients with triple-negative breast cancer?,” published in the International Journal of Cancer, shows that a drug which targets the p53 mutated protein can largely inhibit triple-negative breast cancer cell proliferation and migration, while also promoting programmed cell death.
Currently, the most successful breast cancer treatments target one of three classes of hormone receptors found at the surface of cancer cells — estrogen receptors, progesterone receptors, and HER2 receptors. However, one in every six breast cancer patients do not express any of these receptors in their tumors,making their treatment difficult.
“At the moment the only form of drug treatment available to patients with triple negative breast cancer is chemotherapy,” Naoise Synnott, a PhD student at the Breast-Predict research group at University College Dublin, and the study’s lead author, said in a press release. “While this will work well for some patients, others may find that their cancer cells don’t respond as well as might be hoped to chemo, leading patients suffering the side effects of this treatment without any of the desired outcomes.”
Nearly 80 percent of triple-negative breast cancers carry mutations in the p53 protein, however.
p53, one of the most studied genes in cancer, is a tumor suppressor gene that prevents cancer from arising in a number of ways. These include blocking cell proliferation when DNA damage is found, activating DNA damage repair mechanisms, and initiating programmed cell death if the damage is irreparable. But when the p53 gene is mutated, tumor suppression is severely compromised.
Not surprisingly, most tumors eventually acquire mutations in this gene, as a means of escaping the regulatory powers exerted by p53.
But studies have shown that restoring normal p53 function holds some promise in such tumors. APR-246, in particular, has the ability to bind the mutated p53 protein and induce conformational changes that restore its intended chores, leading to tumor cell cycle arrest and apoptosis.
Using a panel of 18 breast cancer cell lines, the researchers demonstrated that APR-246, an investigational compound, may also work in triple-negative breast cancer cells, inhibiting tumor cell proliferation and migration, and inducing apoptosis in a p53 mutant-dependent manner — the more mutated p53 a cell line had, the better the treatment worked.
“Based on our data, we conclude that targeting mutant p53 with [APR-246] is a potential new approach for treating p53-mutated breast cancer, including the subgroup with triple-negative (TN) disease,” the researchers wrote.