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Experts boost activity of potential therapeutic targets in triple negative breast cancer

CHAMPAGNE, Sick. — Less than 20% of breast cancers diagnosed are defined as «triple negative», lacking the three types of receptors commonly found in other types of breast cancer. However, TNBC’s higher risk recurrence, metastasis, and death rate. In a study conducted in TNBC cells and a mouse model of the disease, researchers found that targeting the estrogen receptor beta in TNBCs altered the activity of dozens of cancer-related genes and slowed the growth and metastasis of these breast cancers.

The study, published in the journal Endocrinology, details many of the gene regulatory changes and anticancer molecular pathways that are activated in response to stimulation and regulation of this estrogen receptor beta protein.

Previous studies said ER beta may have cancer-suppressing effects, but how the receptor contributes to anti-cancer pathways is not well understood. Benita Katzenellenbogena professor molecular and integrative physiology at the University of Illinois Urbana-Champaign, leading new research with the U. of I. chemical teacher John Katzenellenbogen.

“There are relatively few studies on how molecules that bind to and activate ER beta and ER beta affect triple-negative breast cancer,” he said.

Benita Katzenellenbogen said that estrogen receptor alpha, a more widely studied receptor found in at least 70% of breast cancers, shares some similarities with ER beta, but the two are not the same. Both promote changes in gene expression when activated by estradiol, the primary female estrogen. However, ER alpha and ER beta are encoded by different genes and differ in abundance and behavior.

“For example, there is a lot of ER alpha in the liver, but there are places in the brain where ER beta is expressed,” he said. ER alpha activation by estrogen tends to promote breast cancer growth, while ER beta has anti-cancer effects. In TNBC, ER alpha levels are low or absent, but the amount of ER beta varies. People diagnosed with TNBC who have more ER beta expressed in breast cancer tend to survive longer than those with low ER beta levels.

To better understand the molecular pathways driving these differences, the researchers used human TNBC cells grown in the lab so that ER beta levels could be controlled. They also looked at the behavior of TNBC tumors containing varying levels of ER beta in mice. Some of the mice were also treated with chloroindazole, a drug that mimics the activating effects of estradiol on ER beta.

«It’s best to activate ER beta without affecting ER alpha,» said John Katzenellenbogen. «And chloroindazole was one of the best compounds we’ve developed to do that.»

Experiments revealed that hundreds of genes are differentially regulated in cells or tumors that express high levels of ER beta. Some of these genes contribute to – or repress – the proliferation and metastasis of cancer. The team saw greater reductions in tumor growth and metastasis in mice with TNBC tumors containing higher levels of ER beta.

«We started with very low estrogen receptor beta and then increased production of the ER beta protein,» said John Katzenellenbogen. «We next examined how different levels of ER beta affected primary tumor growth and metastatic tumors from the primary tumor. And we found that ER beta suppressed tumor proliferation, invasiveness, and metastasis.»

When researchers further activated the ER beta with chloroindazole, it added to the anti-cancer effects in certain situations.

«Even increasing ER beta to a low level had a significant effect on tumor growth and especially metastasis,» said Benita Katzenellenbogen. «And in many cases, we found that additional administration of chloroindazole gave greater benefit to suppressive activities.» She said treatments change cancer cells, but can also affect other types of cells, such as stromal cells, which support the growth and maintenance of cancer.

Katzenellenbogens said there is still a lot of work to be done to better understand the role of ER beta in certain breast cancers. This research may also be useful in the treatment of other types of cancer, such as ovarian and brain cancers, as well as tissues that express good levels of ER beta receptors.

Researchers from a clinical trial testing the use of estradiol to modulate ER beta activity in TNBC patients. currently underground at the Mayo Clinic. They are not involved in this research, but are looking forward to the results.

The Breast Cancer Research Foundation, the National Institutes of Health, and the Julius and Mary Landfield Cancer Research Fund at the University of Illinois Urbana-Champaign supported this research.

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