Discovery May Overcome Treatment Resistance in Breast Cancer

Investigators have identified 2 cytokines that may play a critical role in the development of treatment-resistant estrogen-driven breast cancers.

Prior research shows a link between the cytokines interleukin 1 beta (IL1β) and tumor necrosis factor alpha (TNFα), and the spread of drug-resistant cancer. But the exact mechanisms that led these molecules to drive drug resistance remained unclear.

In a study published in Molecular Cell, investigators found that IL1β and TNFα activate pathways that modify the shape of the estrogen receptor. This phenomenon appeared to drive resistance to chemotherapy drug tamoxifen.

“Cytokines change the shape of the estrogen receptor, and that changes overrides the inhibitory effects of tamoxifen and leads to drug resistance,” said lead investigator Kendall Nettles. “These findings dramatically alter our understanding of the biological actions of pro-inflammatory cytokines in breast cancer cells.”

The investigators used a combination of genomic, cellular, biochemical, and structural approaches to find that the way the cytokines alter the estrogen receptor is sufficient to induce breast cancer cell growth in the absence of estrogen.

In addition to reversing tamoxifen suppression of growth, cytokine activation of the estrogen receptor also enhanced the invasive properties of MCF-7. MCF-7 is a specific line of human breast cancer cells and is the most studied in the world.

The investigators used X-ray crystallography to develop an atomic snapshot of the estrogen receptor that showed how the shape changes occurred and how the process could be blocked.

Both inflammation and immune cells are known causes of resistance but if the inflammation cannot be blocked, resistance can be reduced or eliminated, according to the authors.

“These tumors can reprogram the immune cells to their advantage so that the cells become tumor supportive,” Nettles said. “We think we can produce hormone therapies that can, in essence, 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.”