Multiple links between stress and breast cancer progression

Friday, 22 March, 2019

Multiple links between stress and breast cancer progression

Scientists have previously demonstrated, in studies with rodents and humans, that stress can exacerbate cancer’s progression, but it wasn’t clear how. Now it appears we finally have some answers, thanks to two separate studies published less than a month apart.

In mid-February, a study led by Chinese researchers established that the stress hormone epinephrine sets off a cascade of biochemical reactions that favour breast cancer growth and spread. Their work was published in The Journal of Clinical Investigation.

The researchers first demonstrated the effects of chronic stress on cancer stem cell growth, in a twist on previous research that did not specifically focus on these self-perpetuating cells. To do this, they induced chronic stress in mice by placing them in small enclosures that limited their movement. All the mice were stressed for a week before being inoculated with either human or mouse breast cancer cells.

After inoculation, the mice were split into two groups: controls, which were moved into large cages; and stressed, which stayed in the small enclosures for an additional 30 days. Confirming the researchers’ expectations, the mice experiencing chronic stress showed behavioural changes consistent with anxiety and depression. They also had bigger, faster-growing tumours and more cancer stem cells than mice in control conditions.

“You can kill all the cells you want in a tumour, but if the stem cells, or mother cells, are not killed, then the tumour is going to grow and metastasize,” said Keith Kelley from the University of Illinois, a co-author on the study. “This is one of the first studies to link chronic stress specifically with the growth of breast cancer stem cells.”

The scientists went on to investigate the underlying biochemical underpinnings that caused stress to increase growth of cancer cells, which until now remained almost completely unknown. Principal investigator Quentin Liu of the Institute of Cancer Stem Cell at Dalian Medical University noted, “A better understanding of the biochemistry that causes stress to increase the growth of cancer cells could lead us toward targeted drug interventions, one of which we discovered in this work.”

Multiple lines of evidence led the scientists towards epinephrine, one of the body’s major stress hormones. First, epinephrine levels were significantly elevated in mice that experienced stress for the duration of the experiment. Second, in stressed mice that received treatments to inactivate the receptor for epinephrine — ADRB2 — tumours were significantly smaller and fewer stem cells were found.

“When most people think of stress, they think it’s cortisol that’s suppressing the immune system,” noted Kelley. “The amazing thing is cortisol was actually lower after a month of stress.”

Once epinephrine binds to one of its two receptors, ADRB2, it elevates levels of an enzyme called lactate dehydrogenase. In normal situations, this enzyme delivers quick energy to muscles in a fight-or-flight situation and produces lactate as a by-product. But cancer cells need lactate for energy. With excessive amounts of lactate dehydrogenase in chronically stressed individuals, cancer-causing genes are activated and cancer cells proliferate.

“These data provide a novel pathway that explains how elevated epinephrine caused by chronic stress promotes breast cancer progression by acting directly on cancer stem cells,” said Liu.

To evaluate the clinical significance of their findings, the scientists measured epinephrine in the blood of 83 human breast cancer patients. Women with high levels of the stress hormone also had high levels of lactate dehydrogenase in biopsied breast cancer tissue, compared with adjacent non-cancerous tissue. Consistent with findings in mice, patients with high serum epinephrine had significantly lower overall survival and disease-free survival compared with patients with low epinephrine levels.

In a final test, the researchers grew breast cancer cells in the lab and introduced a wide variety of FDA-approved cancer drugs. Several treatments, including vitamin C, suppressed lactate dehydrogenase production. When vitamin C was injected into stressed mice, tumours shrank.

“Taken together, these findings show that vitamin C might be a novel and effective therapeutic agent for targeting cancer in patients undergoing chronic stress,” Liu said.

Less than four weeks later, Swiss scientists announced that they had deciphered the molecular mechanisms linking breast cancer metastasis with increased stress hormones. In addition, they found that synthetic derivatives of stress hormones, which are frequently used as anti-inflammatories in cancer therapy, decrease the efficacy of chemotherapy.

One major obstacle in the treatment of metastatic breast cancer is the phenomenon of tumour heterogeneity. As the disease progresses, the tumour becomes more diverse, and the difference between the cancer cells may lead to inadequate treatment.

Because the underlying mechanisms of this phenomenon remain unclear, Professor Mohamed Bentires-Alj and his team from the University of Basel and University Hospital of Basel have been studying the cells of a highly metastatic form of cancer known as triple-negative breast cancer. This cancer type is resistant to standard therapies leaving patients with fewer treatment options.

To explore the heterogeneity between tumours and metastases, the research team profiled the activity of genes in a mouse model of breast cancer. They found that metastases have increased activity of glucocorticoid receptors (GRs), which mediate the effects of stress hormones such as cortisol.

Concentrations of the stress hormones cortisol and corticosterone were higher in mice with metastases that in those with no metastases. The scientists showed that increased levels of these stress hormones activate the GRs, which cause increased colonisation and heterogeneity of the cancer cells — and, ultimately, shortened survival.

GRs also mediate the effects of synthetic derivatives of cortisol such as dexamethasone, which is used widely to treat the side effects of chemotherapy. The research group showed that in mice with metastatic cells, the efficacy of the chemotherapy drug paclitaxel was decreased when administered in combination with dexamethasone.

These findings, published in the journal Nature, suggest that caution should be taken when prescribing glucocorticoid hormones to patients with breast cancer. The study also suggests that GR inhibition may be beneficial for patients and could lead to the development of new therapies to combat breast cancer metastasis.

“Tumour heterogeneity is a serious hurdle for therapy,” said Prof Bentires-Alj. “These findings highlight the importance of stress management in patients — and especially those with triple-negative breast cancer. Moderate exercise and relaxation techniques have been shown to correlate with enhanced quality of life and greater survival in patients.”

Image credit: © Rinder

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