Breast cancer cells hijack natural stress protectors

Washington: Turns out, a member of a protein family known for protecting our cells also protects cancer cells in aggressive, metastatic breast cancer.

According to a new study conducted at the Augusta University, induction of heat shock protein 70, or HSP70, – which protects cells from stress – appeared to be a key difference between difficult-to-treat triple negative breast cancer and the more responsive estrogen-positive breast cancer.

“This aggressive breast cancer hijacks your normal protective physiological process to survive the toxic environment it has created,” said researcher Hasan Korkaya.

The finding illustrated at least one-way tumour necrosis factor alpha, or TNFa – which as its name implies can cause cancer cells to self-destruct – is manipulated by cancer to instead aid its survival.

It also provides evidence that targeting HSP70 could be an effective strategy for some of the most aggressive breast cancers.

The researchers have found that to aid cancer, TNFa first induces the protein A20, which in turn induces HSP70. A20 is a failsafe mechanism immune cells use after aggressively attacking an invader, like a bacterium, to stop expressing things like cytokines used to kill the invader so they do not instead begin attacking the body. In fact, for autoimmune diseases like lupus and rheumatoid arthritis, where the immune system is attacking the body, a major treatment is TNFa blockers.

A20 has not been linked to HSP70 in immune cells, but the new work indicates a powerful partnership in aggressive breast cancer cells that essentially shuts off cell death.

“We think A20 determines TNFa activity in different tumor types,” Korkaya noted. “The cancer cell cannot induce apoptosis, it cannot die.”

To make matters worse, the partnership also promoted a cancer stem cell type that makes the durable cells more aggressive and able to spread.

In less-aggressive luminal breast cancer, TNFa doesn’t upregulate A20, rather helps cancer cells commit suicide, they report. But when the scientists overexpressed A20 in these luminal breast cancer cells, they started functioning more like their aggressive counterparts.

When they inhibited A20 expression, they gave more TNFa to the aggressive cells, the previously diligent cancer cells started dying off. But when they gave TNFa without first inhibiting A20, the cancer cells produced even more of the protective protein.

Study co-author Jason E. Gestwicki, provided an HSP70 inhibitor he developed for the studies.
Breast cancer is the second leading cause of cancer death among women, just behind lung cancer, according to the American Cancer Society. Triple-negative breast cancer accounts for about 15-20 per cent of breast cancer cases and is typically treated with a combination of surgery, chemotherapy and radiation therapy.

Autoimmune diseases like lupus are known to have gene mutations in the multifunctional A20.
HSP70 is found in high levels in a lot of tumour types and those high levels typically correlate with metastasis and a poor prognosis. HSP70 inhibitors already are in clinical trials for cancers like non-small cell lung cancer.

Many of our cell types use one or more of the heat shock proteins to protect themselves from extremes like cold, heat and too little oxygen. Their diverse functions include aiding the proper folding of proteins, the workhorse of cells, so the protein performs the proper job.

Misfolding, for example, can result in a variety of conditions from Alzheimer’s to cancer. Cancer cells use heat shock proteins to enable their successful growth and spread and even to help them become treatment resistant.

The findings appeared in the Journal of Oncogene.