Aggressive breast cancer cells divert a natural protector from stress to flourish

AUGUSTA, Georgia (October 2, 2018) – A member of a family of proteins known to protect our cells also protects cancer cells in cases of metastatic and aggressive breast cancer, scientists report.

The induction of heat shock protein 70, or HSP70, – which protects cells from stress – appears to be an essential difference between difficult to treat triple-negative breast cancer and breast cancer more sensitive to positive estrogen, says Dr. Hasan Korkaya, tumor biologist at the Georgia Cancer Center and the Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University.

"This aggressive breast cancer diverts your normal protective physiological process to survive in the toxic environment that it has created," Korkaya said.

The discovery illustrates at least one way that tumor necrosis factor alpha, or TNFα – which, as its name suggests, can cause self-destruction of cancer cells – is manipulated by cancer to contribute to its survival .

"We show here that TNFα supports aggressive breast cancer by first regulating A20, which induces HSP70, which protects cancer cells from TNFα-induced apoptosis," states first author Eunmi Lee, PhD student in biochemistry and cancer biology at the AU Graduate School. working in the Korkaya laboratory.

It also provides evidence that targeting HSP70 could be an effective strategy for some of the most aggressive breast cancers, they report in the newspaper. oncogenic.

Scientists, working on animal models and human breast cancer cell lines, have already begun using HSP70 inhibitors, examining both efficacy and toxicity, before giving more TNFα, which should then be free to kill rather than protect the cancer.

They discovered that, to help cancer, TNFα first induces A20 protein, which in turn induces the HSP70 virus. A20 is a fail-safe mechanism that immune cells use after aggressively attacking an invader, such as a bacterium, to stop expressing things such as the cytokines used to kill the invader so as not to attack the body at all. the place. In fact, for autoimmune diseases such as lupus and rheumatoid arthritis, where the body's immune system attacks the body, a major treatment is anti-TNFα, notes Korkaya.

A20 has not been associated with HSP70 in immune cells, but the new work indicates a powerful partnership in aggressive breast cancer cells that essentially prevents cell death.

"We believe that A20 determines the activity of TNFα in different types of tumors," Korkaya says. "The cancer cell can not induce apoptosis, it can not die."

To make matters worse, the partnership also promotes a type of cancer stem cell that makes the cells more aggressive and more capable of spreading.

"Not only are breast cancer cells protected, but they are also becoming more aggressive," Korkaya said. They are still trying to find out why TNFα induces A20 in this scenario. He notes that the constant up-regulation of HSP70 by A20 is important for cancer, as the heat shock protein degrades so rapidly.

In less aggressive luminal breast cancer, TNFα does not increase the regulation of A20, but rather helps cancer cells to commit suicide, they reported. But when scientists overexpressed A20 in these breast cancer cells, they began to function more like their aggressive counterparts.

When they inhibited the expression of A20, then gave more TNFα to aggressive cells, previously diligent cancer cells began to die. But when they gave TNFα without first inhibiting A20, the cancer cells produced even more of the protective protein.

Why does TNFα not increase A20 and HSP70 levels in luminal breast cancer? That's another question they want to answer. They also want to check if the A20 is upregulated in patients whose disease has progressed and suspect that they will find it.

The study's co-author, Dr. Jason E. Gestwicki, a professor at the Institute of Neurodegenerative Diseases at the University of California at San Francisco, has provided an HSP70 inhibitor that has been found to be inactive. he has developed for studies.

Breast cancer is the second leading cause of cancer death in women, just behind lung cancer, according to the American Cancer Society. According to the Susan G. Komen® organization, triple-negative breast cancer accounts for approximately 15 to 20% of breast cancer cases and is typically treated with a combination of surgery, chemotherapy and radiation therapy.

Autoimmune diseases such as lupus are known to have gene mutations in multifunctional A20. Missing A20 mice suffer from multi-organ inflammation and death, but it has been shown that his habitual ability to activate inflammation promotes liver regeneration.

HSP70 is present at high levels in many types of tumors and these elevated levels are usually related to metastases and poor prognosis. Inhibitors of HSP70 are already undergoing clinical trials for cancers such as non-small cell lung cancer.

Many of our cell types use one or more of the heat shock proteins to protect themselves from extremes such as cold, heat, and lack of oxygen. Their various functions include helping the proper protein folding, the spearhead of cells, so that the protein fulfills its role. A bad folding, for example, can lead to various conditions, from Alzheimer's disease to cancer. Cancer cells use heat shock proteins to allow them to grow and spread, and even to help them become resistant to treatment.

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The research was funded by the Susan G. Komen® organization and the American Cancer Society.

See the study published here https: //www.nature.com /articles/s41388-018-0472-0.epfd? author_access_token =aJ8BBKQJJ.