The majority of breast cancers are estrogen-receptor positive and often treated with anti-estrogen drugs such as tamoxifen. However, resistance to the hormone therapy eventually develops in a large number of patients, leaving them with few options. Now, new research reveals a molecular explanation for this type of drug resistance and could lead to new therapies and better treatment decisions for estrogen-driven breast tumors.

breast cancer text pink ribbon and pillsShare on Pinterest
Researchers hope that their discovery will lead to new treatments that overcome drug resistance in ER+ breast cancers.

A report on the findings – by a team that includes researchers from The Scripps Research Institute (TSRI) in Jupiter, FL – is published in the journal Molecular Cell.

Around 80 percent of breast cancers are estrogen-receptor positive (ER+) – that is, tumor growth is driven by the hormone estrogen.

A hormone is a signaling molecule that alters the activity of cells and organs.

The tumor grows because the breast cancer cells contain proteins called estrogen receptors that become active when estrogen molecules attach to them.

Once activated, the estrogen receptors on the tumor cells alter the expression of genes that spur cell growth.

Estrogen-positive breast cancers are frequently treated with drugs that suppress estrogen receptor activity.

Unfortunately, large numbers of patients eventually develop resistance to these treatments, leaving them with few alternatives.

In recent years, many researchers have been working to understand the underlying mechanisms of resistance to hormone therapy in breast cancer. One of their main discoveries is that the molecular biology is highly complex and diverse.

The new study concerns two cytokines, or small signaling proteins, called interleukin 1 beta (IL1β) and tumor necrosis factor alpha (TNFα).

These pro-inflammatory immune system molecules are thought to be involved in the spread of drug-resistant tumors, but the underlying mechanisms have been somewhat of a mystery.

The team found that IL1β and TNFα switch on pathways that change the structure of the estrogen receptor on the breast cancer cells.

This change appears to be the reason that the tumor develops resistance to the anti-estrogen drug tamoxifen, as Kendall Nettles, one of the study leaders and associate professor at TSRI, explains:

“Cytokines change the shape of the estrogen receptor, and that change overrides the inhibitory effects of tamoxifen and leads to drug resistance.”

For their investigation, Prof. Nettles and colleagues used a combination of cellular, genomic, biochemical, and structural tools to probe the interaction between the cytokines and the estrogen receptor.

They found that the way the molecules interfere with the estrogen receptor is sufficient to stimulate the breast cancer cells to grow – even without estrogen, which is what happens when tumors are initially treated with anti-estrogen drugs such as tamoxifen.

The team also discovered that not only did the cytokines undermine the growth-suppression effects of tamoxifen, but their activation of the estrogen receptor also encouraged a well-studied type of human breast cancer cell known as MCF-7 to become more invasive.

Finally, with the help of X-ray crystallography, the researchers produced atomic-level snapshots of how the estrogen receptor structure changed under the influence of the cytokine signals, offering valuable clues as to how they might be blocked.

Prof. Nettles says that he and his colleagues believe it is possible to develop new hormone therapies that reprogram the immune system so that it does not alter the structure of the estrogen receptor in the first place.

They also suggest – from what they can see on their atomic snapshots – that the same mechanism may be responsible for driving resistance to cancer drugs that target receptors such as Her2Neu and other growth promoters.

These findings dramatically alter our understanding of the biological actions of pro-inflammatory cytokines in breast cancer cells.”

Prof. Kendall Nettles

Learn how nanodelivery of a new drug shows promise in the treatment of triple-negative breast cancer.