Triple-negative breast cancer thrives by producing its own growth factors

Triple-negative breast cancer cells produce inflammatory cytokines Interleukin-6 (IL-6) and Interleukin-8 (IL-8), which in turn stimulate the growth of cancer cells, according to a study published in the June issue of Cancer Research, a publication of the American Association for Cancer Research.

The study identified new targeted therapies for patients with triple-negative breast cancer focused on signaling molecules called cytokines, which are essentially hormones produced by the cells to tell breast cancer cells to grow.

"Currently, there are no effective targeted therapies for triple-negative breast cancer, and this type of breast cancer is most associated with lack of response to therapy and poor prognosis," says Powel Brown, M.D., Ph.D., professor and chair of Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center and senior author on the study conducted with colleagues at MD Anderson and Baylor College of Medicine.

"There are no prevention strategies for this form of breast cancer," Brown said. "We use non-specific chemotherapy on all stage II or higher triple-negative breast cancer patients."

Triple-negative breast cancer lacks hormonal and growth factor drug targets present in most breast cancers, making it the deadliest form of the disease, typically diagnosed in women under the age of 50 and accounting for 15 to 20 percent of breast cancer deaths annually. Although there is a high incidence in both Hispanic and African-American women, African-American and women from Africa are more likely to die from this disease. Sibling molecules; maximum impact Brown and his collaborators used cell lines and mouse models to define the cytokines produced by triple-negative breast cancer. They found IL-6 and IL-8 were most highly produced and each hormone is an independent growth factor for breast cancer.

"There has been a previous understanding among some researchers that macrophages, inflammatory cells in the body, may produce cytokines IL-6 and IL-8," says Brown. "Interestingly enough, this study demonstrated that breast cancer cells themselves produce these hormones; essentially producing their own growth factor."

Previous research also found that IL-6 is particularly important for cancer stem cells, which tend to repopulate cancer after it becomes resistant to chemotherapy.

This study also found strategies that can be used to target the hormones' ability to stimulate cancer, including blocking the cytokines' receptors, suppressing the production of the IL-6 hormone, or blocking an intracellular signaling molecule that transmits the IL-6 and IL-8 signal to tell the cell to grow.

"Any of those strategies causes the suppression of triple-negative breast cancer growth," says Brown. "There are available antibodies to the IL-6 receptor and inhibitors of the intracellular kinases called STAT proteins. These drugs are available for clinical trials to treat triple-negative breast cancer."

Brown, who is also on the Scientific Advisory Board of Susan G. Komen for the Cure, says suppression of both hormones would be more effective than targeting just one. "If you inhibit either IL-6 or the IL-8 you get an inhibition of the cancer, but if you inhibit both of them, you get maximum inhibition of the cancer," he says.

Targeted therapies for the most aggressive breast cancer The research study team is funded by a Susan G. Komen Promise Grant - a grant intended to support collaborative, multi-disciplinary research programs integrating clinical and lab settings while addressing critical issues in breast cancer research. "The Promise Grant allows us to use genomic technologies at the DNA and RNA level to identify new targets for treatment and prevention of this disease."

With this type of supported research, Brown and his colleagues have been able to identify in another clinical trial that a kinase inhibitor was effective in the treatment of triple-negative breast cancer, shrinking tumors in 10 percent of triple-negative breast cancer patients. "This research led us to the opportunity to test our theory that triple-negative breast cancer expresses cytokines," said Brown.

Looking ahead, Brown anticipates these results will lead to the development of clinical trials targeting both of IL-6 and IL-8 and possibly testing a STAT inhibitor for triple-negative breast cancer.