Researchers discover key to drug resistance in common breast cancer treatment

March 20, 2017, The Scripps Research Institute
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

Compound in citrus oil could reduce dry mouth in head, neck cancer patients

May 21, 2018
A compound found in citrus oils could help alleviate dry mouth caused by radiation therapy in head and neck cancer patients, according to a new study by researchers at the Stanford University School of Medicine.

Scientists reveal likely cause of childhood leukaemia

May 21, 2018
A major new analysis reveals for the first time the likely cause of most cases of childhood leukaemia, following more than a century of controversy about its origins.

Ice cream funds research showing new strategy against thyroid cancer

May 21, 2018
Anaplastic thyroid cancer is almost uniformly fatal, with an average lifespan of about 5 months after diagnosis. And standard treatment for the condition includes 7 weeks of radiation, often along with chemotherapy.

Bladder cancer model could pave the way for better drug efficacy studies

May 21, 2018
Understanding that not all bladder cancers are the same, researchers at the University of North Carolina Lineberger Comprehensive Cancer Center have created a tool that may help them to uncover why only a fraction of patients ...

MR spectroscopy imaging reveals effects of targeted treatment of mutant IDH1 gliomas

May 18, 2018
Using a novel imaging method, a Massachusetts General Hospital (MGH) research team is investigating the mechanisms behind a potential targeted treatment for a subtype of the deadly brains tumors called gliomas. In their report ...

Particle shows promise to prevent the spread of triple-negative breast cancer

May 18, 2018
USC researchers have pinpointed a remedy to prevent the spread of triple-negative breast cancer. Metastatic breast cancer is a leading cause of death for women. The findings appear today in Nature Communications.

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.