Cytokines modify the shape of estrogen receptors and drive resistance

Researchers have found two molecules in the immune system that may be the key to the development of drug resistance in estrogen-driven breast cancers, according to a new study published in the journal Molecular Cell.

Cytokines interleukin 1 beta (IL1β) and tumor necrosis factor alpha (TNFα) have been linked to the spread of drug-resistant cancer, but the exact mechanism of the resistance is not well understood. This new research may lead to novel therapeutic approaches and influence treatment decisions for thousands of patients.

Nearly 75% of all breast cancer tumors are driven by estrogen. These tumors are frequently treated with the intent of suppressing estrogen receptor activity, but at least half of patients do not respond.

The new study states that IL1β and TNFα turn on pathways that modify the shape of the estrogen receptor. This phenomenon may drive resistance to tamoxifen.

“Cytokines change the shape of the estrogen receptor, and that change overrides the inhibitory effects of tamoxifen and leads to drug resistance,” said Kendall Nettles, PhD, associate professor at The Scripps Research Institute (TSRI), and one of the leaders of the new study. “These findings dramatically alter our understanding of the biological actions of pro-inflammatory cytokines in breast cancer cells.”

The researchers used a combination of genomic, cellular, biochemical, and structural approaches to determine that the way the cytokines alter the estrogen receptor is sufficient to induce growth of breast cancer cells in the absence of estrogen. This is precisely what occurs when breast cancer is initially treated with an endocrine therapy such as tamoxifen.

In addition to reversing tamoxifen suppression of growth, cytokine activation of the estrogen receptor also enhanced the invasive properties of a specific line of human breast cancer cells known as MCF-7.

With the use of x-ray crystallography, Nettles and his colleagues developed an atomic snapshot of the estrogen receptor that showed how the changes in shape occur, and potential ways that the process could be blocked.

Nettles stated that both inflammation and immune cells are known causes of resistance, but if that inflammation can be blocked then resistance can be reduced or eliminated.

“These tumors can reprogram the immune cells to their advantage so that the cells become tumor supportive,” he said. “We think we can produce hormone therapies that can, in essence, re-reprogram the immune system or prevent it from altering the receptor in the first place, which is an obvious strategy for blocking these adverse effects. Importantly, our atomic snapshot of the receptor showed that the same mechanism can explain how Her2Neu or other growth promoting factors, as well as certain invasion and motility signals also cause resistance to anti-hormone therapies.”

Scientists from the Florida campus of TSRI, the University of California, San Diego, and the University of Illinois contributed to the research. Research was supported by the National Institutes of Health, Frenchman’s Creek Women for Cancer Research, and The BallenIsles Men’s Golf Association.