Recently, researchers have discovered that the hormone progesterone might stimulate the growth of breast cancer cells that are resistant to anti-estrogen therapy and chemotherapy. However, additional hormones, including stress hormones often used to treat chemotherapy side effects, may reduce the efficacy of these drugs in some women with breast cancer, according to new research published in Oncogene.
"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," Hallgeir Rui, MD, PhD, a Professor of Cancer Biology, Pathology and Medical Oncology at Thomas Jefferson University, said in a press release. "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 estrogen receptor (ER) positive disease. This group of women can successfully keep the growth of their cancer in check with therapies that block estrogen receptors. While some women can use hormone blockers such as tamoxifen or aromatase inhibitors to control their cancer for a decade or more, one of four will develop resistance.
Researchers believe that some of this resistance is caused by CK5 cells in the tumor, which harbor the ability to resist estrogen-blocking therapy and chemotherapy. Dr. Rui estimates that 10% to 15% of patients with ER-positive disease harbor CK5 cells.
Earlier work 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 wasn't a major concern. Progesterone, however, belongs to the 3-ketosteroids family of hormones 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, increased the number of CK5-cell 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," researcher Chelain Goodman, an MD/PhD student in Dr. Rui's lab, said in a press release. "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.”
Dr. Rui and colleagues turned to the hormone prolactin to see if they could counteract the effect of the stress hormones. When Dr. Rui and colleagues added prolactin to the cells exposed to 3-ketosteroids, the expansion of CK5 cells was prevented. Prolactin helped keep the breast cells mature, and made the environment unfavorable for growth of the immature-CK5 cells.
"Although prolactin appears to be an excellent candidate to counteract the effect of stress hormones on women with this subtype of breast cancer, the hormone can also drive other types of breast cancer, so we must proceed with caution.” Dr. Rui said in a press release, “An alternative possibility supported by this research is inhibiting a protein called BCL6 that appears to be critical for steroid-induction of CK5 cells. Perhaps the simplest solution would be to seek alternatives to steroids for controlling the side-effects of chemotherapy in patients with this tumor subtype."
The group has already found two potential biomarkers in clinical samples that would help identify ER-positive tumors with CK5 cells and are looking into validating their findings in clinical trials.
Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERα and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo.