Researchers discover key to drug resistance in common breast cancer treatment

March 20, 2017
Micrograph showing a lymph node invaded by ductal breast carcinoma, with extension of the tumour beyond the lymph node. Credit: Nephron/Wikipedia

Three-quarters of all breast cancer tumors are driven by the hormone estrogen. These tumors are frequently treated with drugs to suppress estrogen receptor activity, but unfortunately, at least half of patients do not respond to these treatments, leaving them with drug-resistant tumors and few options.

Now, scientists from the Florida campus of The Scripps Research Institute (TSRI), the University of California (UC), San Diego and the University of Illinois have found that two immune system molecules may be key to the development of drug resistance in estrogen-driven breast cancers. The researchers believe this finding may open the door to novel therapeutic approaches and influence treatment decisions for the tens of thousands of patients who suffer from estrogen-driven breast cancers.

These molecules, which are cytokines called interleukin 1 beta (IL1β) and tumor necrosis factor alpha (TNFα), had previously been linked to the spread of drug-resistant , but scientists were unsure of the exact mechanisms that led these molecules to drive drug resistance.

The new study, published online ahead of print in the journal Molecular Cell, reveals that IL1β and TNFα turn on pathways that modify the actual shape of the estrogen receptor. This phenomenon appears to drive resistance to the common anti-cancer drug tamoxifen.

"Cytokines change the shape of the estrogen receptor, and that change overrides the inhibitory effects of tamoxifen and leads to ," said TSRI Associate Professor Kendall Nettles, who led the new study alongside senior author Christopher K. Glass and study first author Joshua D. Stender of UC San Diego. "These findings dramatically alter our understanding of the biological actions of pro-inflammatory cytokines in cells."

Striking Back at Drug Resistance

Using a combination of genomic, cellular, biochemical and structural approaches, the researchers found that the way these cytokines alter the estrogen receptor are sufficient to induce growth of in the absence of estrogen, precisely what happens when breast cancer is initially treated with an endocrine therapy like tamoxifen. Scientists found that 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, the most studied human cancer cell in in the world.

Using x-ray crystallography, Nettles and his colleagues developed an atomic snapshot of the to show how these shape changes occur and how the process might be blocked.

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

"These tumors can reprogram the immune cells to their advantage so that the become tumor supportive," Kettles 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."

Explore further: New insights into mechanisms of breast cancer development and resistance to therapy

Related Stories

New insights into mechanisms of breast cancer development and resistance to therapy

January 9, 2017
Why does breast cancer develop and how come certain patients are resistant to established therapies? Researchers from the University of Basel have gained new insights into the molecular processes in breast tissue. They identified ...

Tamoxifen resistance linked to high estrogen levels in utero

September 8, 2016
An animal study suggests that resistance to tamoxifen therapy in some estrogen receptor positive breast cancers may originate from in utero exposure to endocrine disrupting chemicals. The study provides a new path forward ...

Osteoporosis drug stops growth of breast cancer cells, even in resistant tumors

June 15, 2013
A drug approved in Europe to treat osteoporosis has now been shown to stop the growth of breast cancer cells, even in cancers that have become resistant to current targeted therapies, according to a Duke Cancer Institute ...

Scientists predict cell changes that affect breast cancer growth, opening door to more effective therapies

April 28, 2016
Designing effective new drugs, especially drugs to fight cancer, demands that you know as much as you can about the molecular workings of cancer growth. Without that, it's like planning to fight a war against an enemy you've ...

Recommended for you

MRI contrast agent locates and distinguishes aggressive from slow-growing breast cancer

September 25, 2017
A new magnetic resonance imaging (MRI) contrast agent being tested by researchers at Case Western Reserve University not only pinpoints breast cancers at early stages but differentiates between aggressive and slow-growing ...

Alternative splicing, an important mechanism for cancer

September 22, 2017
Cancer, which is one of the leading causes of death worldwide, arises from the disruption of essential mechanisms of the normal cell life cycle, such as replication control, DNA repair and cell death. Thanks to the advances ...

'Labyrinth' chip could help monitor aggressive cancer stem cells

September 21, 2017
Inspired by the Labyrinth of Greek mythology, a new chip etched with fluid channels sends blood samples through a hydrodynamic maze to separate out rare circulating cancer cells into a relatively clean stream for analysis. ...

Whole food diet may help prevent colon cancer, other chronic conditions

September 21, 2017
A diet that includes plenty of colorful vegetables and fruits may contain compounds that can stop colon cancer and inflammatory bowel diseases in pigs, according to an international team of researchers. Understanding how ...

Drug combination may improve impact of immunotherapy in head and neck cancer

September 21, 2017
Checkpoint inhibitor-based immunotherapy has been shown to be very effective in recurrent and metastatic head and neck cancer but only in a minority of patients. University of California San Diego School of Medicine researchers ...

New kinase detection method helps identify targets for developing cancer drugs

September 21, 2017
Purdue University researchers have developed a high-throughput method for matching kinases to the proteins they phosphorylate, speeding the ability to identify multiple potential cancer drug targets.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.