Triple negative breast cancer cells showing abnormal expression basal-like markers not found on normal breast epithelial cells. Cells are stained with cytokeratins 14 (green) and 19 (red). Photo courtesy: Bill Schmitt.
Triple negative breast cancer cells showing abnormal expression basal-like markers not found on normal breast epithelial cells. Cells are stained with cytokeratins 14 (green) and 19 (red). Photo courtesy: Bill Schmitt.

Although radiation is successfully used to treat breast cancer, inflammation caused as a side-effect of radiation may have an adverse effect, promoting the survival of triple-negative breast cancer cells.

This is the conclusion of a study by Jennifer Sims-Mourtada, Ph.D., director of Translational Breast Cancer Research at ChristianaCare’s Helen F. Graham Cancer Center & Research Institute, published online in the International Journal of Radiation Biology.[1]

Triple-negative breast cancer is cancer that tests negative for estrogen receptors, progesterone receptors, and excess human epidermal growth factor receptor 2 (HER2) protein. As a result, the growth of this cancer is not fueled by the hormones estrogen and progesterone, or by the HER2 protein. These cancers tend to be more common in women under age 40, who are African-American, Latina, or who carry a mutated BRCA1 gene.

Triple-negative breast cancer accounts for 15-20% of all breast cancers and is faster growing than other types of breast cancers.

Sims-Mourtada’s latest study helps scientists to better understand the mechanisms behind the development of this aggressive and hard-to-treat cancer. It shows that inflammation caused by radiation can trigger stem-cell-like characteristics in non-stem breast cancer cells.[1]

Jennifer Sims-Mourtada, Ph.D., in the lab at ChristianaCare's Cawley Center for Translational Cancer Research. Photo Courtesy: 2020 | ChristianaCare's Cawley Center for Translational Cancer Research
Jennifer Sims-Mourtada, Ph.D., in the lab at ChristianaCare’s Cawley Center for Translational Cancer Research. Photo Courtesy: 2020 | ChristianaCare’s Cawley Center for Translational Cancer Research

The good and the bad
“This is the good and the bad of radiation,” Sims-Mourtada noted. “We know radiation-induced inflammation can help the immune system to kill tumor cells — that’s good — but also it can protect cancer stem cells in some cases, and that’s bad.”

“What’s exciting about these findings is we’re learning more and more that the environment the tumor is in – its microenvironment – is very important. Historically, research has focused on the genetic defects in the tumor cells. We’re now also looking at the larger microenvironment and its contribution to cancer,” she added.

“My work focuses on cancer stem cells and their origination. [These cells] exist in many cancers, but they’re particularly elusive in triple-negative breast cancer. Their abnormal growth capacity and survival mechanisms make them resistant to radiation and chemotherapy and help drive tumor growth,” Sims-Mourtada explained.

The researchers applied radiation to triple-negative breast cancer stem cells and to non-stem cells. In both cases, they found radiation-induced an inflammatory response that activated the Il-6/Stat3 pathway, which plays a significant role in the growth and survival of cancer stem cells in triple-negative breast cancers. They also found that inhibiting STAT3 blocks the creation of cancer stem cells. As yet unclear is the role IL-6/STAT3 plays in transforming a non-stem cell to a stem-cell.

Delaware
For women living in Delaware, Sims-Mourtada’s research is especially urgent: The rates of triple-negative breast cancer in the state are the highest nationwide.

“At ChristianaCare, we are advancing cancer research to help people in our community today, while we also advance the fight against cancer nationwide,” said Nicholas J. Petrelli, M.D., Bank of America endowed medical director of the Helen F. Graham Cancer Center & Research Institute.

“Sims-Mourtada’s research is a dramatic step toward better treatments for triple-negative breast cancer,” Petrelli concluded.

To advance her research on inflammation, last year Sims-Mourtada received a US $ 659,538 grant from the Lisa Dean Moseley Foundation. The three-year grant will enable her and her team at the Cawley Center for Translational Cancer Research to continue investigating the role of cells immediately around a tumor in spurring the growth of triple-negative breast cancer and possible therapy for this particularly difficult to treat cancer.

“Our next step is to understand the inflammatory response and how we might inhibit it to keep new cancer stem cells from developing,” Sims-Mourtada said.

The researchers previously identified an anti-inflammatory drug, currently used to treat rheumatoid arthritis, that has the potential to target and inhibit the growth of cancer stem cells and triple-negative breast cancer tumors. That research could set the stage for clinical investigation of the drug, alone or in combination with chemotherapy, to improve outcomes for patients with triple-negative breast cancer.

Reference
[1] Arnold KM, Opdenaker LM, Flynn NJ, Appeah DK, Sims-Mourtada J. Radiation induces an inflammatory response that results in STAT3-dependent changes in cellular plasticity and radioresistance of breast cancer stem-like cells [published online ahead of print, 2020 Jan 6]. Int J Radiat Biol. 2020;1–14. doi:10.1080/09553002.2020.1705423 [Pubmed][Article]