Toughest Breast Cancer May Have Met Its Match

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Fast Facts: Only 20 percent of patients with so-called triple-negative breast cancer respond fully to chemotherapy. New research shows that chemotherapeutic drugs stimulate the HIF protein network in the cancer cells, enhancing their ability to survive. Giving HIF inhibitors together with traditional chemotherapy decreased tumor size in mice.

Newswise Triple-negative breast cancer is as bad as it sounds. The cells that form these tumors lack three proteins that would make the cancer respond to powerful, customized treatments. Instead, doctors are left with treating these patients with traditional chemotherapy drugs that only show long-term effectiveness in 20 percent of women with triple-negative breast cancer. Now, researchers at The Johns Hopkins University have discovered a way that breast cancer cells are able to resist the effects of chemotherapy and they have found a way to reverse that process.

A report of their findings was published online in the journal Proceedings of the National Academy of Sciences on Dec. 1.

Triple-negative breast cancers account for about 20 percent of all breast cancers in the United States, and 30 percent of all breast cancers in African-American women. In addition to being resistant to chemotherapy, they are known to include a high number of breast cancer stem cells, which are responsible for relapses and for producing the metastatic tumors that lead to the death of patients with cancer. Previous research revealed that triple-negative breast cancer cells show a marked increase in the activity of many genes known to be controlled by the protein hypoxia-inducible factor (HIF). Given these past results, a research team directed by Gregg Semenza, M.D., Ph.D., decided to test whether HIF inhibitors could improve the effectiveness of chemotherapy.

Our study showed that chemotherapy turns on HIF and that HIF enhances the survival of breast cancer stem cells, which are the cancer cells that must be killed to prevent relapse and metastasis, says Semenza, the C. Michael Armstrong Professor of Medicine at Johns Hopkins and a Johns Hopkins Kimmel Cancer Center expert. The good news is that we have drugs that block HIF from acting.

Semenzas study began by treating lab-grown triple-negative breast cancer cells with the chemotherapy drug paclitaxel and looking for changes in HIF levels. After four days of treatment, HIF protein and activity levels had increased, as had the percentage of breast cancer stem cells among the surviving cells. When Semenzas team, led by postdoctoral fellow Debangshu Samanta, Ph.D., genetically altered the cancer cells to have less HIF, the cancer stem cells were no longer protected from death by chemotherapy, demonstrating that HIF was required for the cancer stem cells to resist the toxic effects of paclitaxel, Semenza says.

At the molecular level, the team found that one of the ways HIF enhances the survival of the stem cells is by increasing the levels of a protein, multidrug resistance protein 1 (MDR1), which acts like a pump to expel chemotherapy from cancer cells. However, when triple-negative breast cancer cells were given paclitaxel plus the HIF inhibitor digoxin, MDR1 levels went down rather than up.

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Toughest Breast Cancer May Have Met Its Match