Stress hormones could undermine breast cancer therapy

Stress hormones, which are frequently used to treat the side effects of chemotherapy, could make effective cancer drugs fail sooner in some women with breast cancer, according to research published in Oncogene (2015; doi:10.1038/onc.2015.193).

"The data we have collected suggests that hormones used in breast cancer treatment, which are also produced by the body in response to stress, could have a major impact on disease progression and outcomes in some patients," said Hallgeir Rui, MD, PhD, a professor of Cancer Biology, Pathology and Medical Oncology at Thomas Jefferson University in Philadelphia, PA. "However, these studies must be confirmed in clinical trials with patients before any new treatment recommendations can be made."

About 70% to 80% of all invasive breast cancers are driven by the hormone estrogen; they are often called estrogen receptor (ER)-positive disease. The growth of these cancers can be successfully kept in check with therapies that block estrogen receptors, or block the production of estrogen in the body, essentially starving the cancer. While some women can use hormone blockers such as tamoxifen or aromatase inhibitors to control their cancer for a decade or more, one out of four patients will develop resistance.

Researchers believe that some of this resistance is caused by a small subpopulation of cancer cells within the tumor called CK5 cells which harbor the ability to resist estrogen-blocking therapy and chemotherapy. When these cells become more abundant, tumors become therapy-resistant. Dr. Rui estimates that 10% to 15% of patients with ER-positive disease harbor CK5 cells.

Earlier work by Dr. Rui and others had shown that progesterone spurs the growth of CK5 cells in breast cancer. But since most ER-positive breast cancers are diagnosed after menopause when progesterone production has stopped, this was not a major concern.

Progesterone, however, belongs to a family of hormones called 3-ketosteroids that are often produced by the body in times of stress. Dr. Rui and colleagues decided to test whether other members of the 3-ketosteroid family, including glucocorticoids used to treat nausea and other breast cancer treatment–related symptoms, might also expand the population of CK5 cells.

Dr. Rui and colleagues exposed breast cancer cell lines to four 3-ketosteroids. Two of the steroids, dexamethasone and aldosterone, boosted CK5-cell numbers by as much as four to seven times. The researchers also confirmed their results in human breast cancer grown in mice, showing increased growth of therapy-resistant tumors in mice treated with dexamethasone and aldosterone.

"Not only are these steroids sometimes used in cancer treatment, glucocorticoid hormones are also naturally produced by the body in response to stress," said first author Chelain Goodman, an MD/PhD student in Dr. Rui's lab.

"Women with breast cancer experience greater levels of stress and studies have shown that this stress can negatively impact their treatment. Glucocorticoids are also widely prescribed for common diseases, including many chronic rheumatoid or autoimmune diseases which can co-occur with breast cancer.”

"This research helps pinpoint a new mechanism behind therapy-resistance in patients with this subtype of ER-positive breast cancer containing CK5 cells and suggests a way to counteract the effect," Goodman added.

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