The hormone progesterone, which is an ingredient in contraceptives and menopausal hormone replacement therapies, may stimulate growth of breast cancer cells that are resistant to anti-estrogen therapy and chemotherapy, recent research has discovered.
Now, new research shows that additional hormones, including stress hormones that are frequently used to treat the side effects of common chemotherapy, could make these effective cancer drugs fail sooner in some women with breast cancer.
However, there may be methodss of counteracting the effect.
Hallgeir Rui, M.D., Ph.D., a Professor of Cancer Biology, Pathology and Medical Oncology at Thomas Jefferson University, said:
“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. However, these studies must be confirmed in clinical trials with patients before any new treatment recommendations can be made."
Estrogen Receptor Positive Disease
The hormone estrogen drives about 70-80 percent of all invasive breast cancers, known as estrogen receptor (ER) positive disease.
This cohort of women can keep the growth of their cancer in check successfully using 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 of four will develop resistance.
It is believed that some of the resistance is due to a small sub-population 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 10-15 percent of patients with ER+ disease carry CK5 cells.
Previous studies by the Rui laboratory 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 wasn’t 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.
Therapy-resistant Tumor Growth
Dr. Rui and the team 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 verified their results in human breast cancer grown in mice, showing increased growth of therapy-resistant tumors in mice treated with dexamethasone and aldosterone.
First author Chelain Goodman, an M.D./Ph.D. student in Dr. Rui’s lab, said:
“Not only are these steroids sometimes used in cancer treatment, glucocorticoid hormones are also naturally produced by the body in response to stress."
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.
To counter the effect of these stress hormones, Dr. Rui and colleagues turned to another hormone, called prolactin. Prolactin is best known for helping women produce milk after childbirth, but it has the additional ability to maintain cell maturity.
CK5 cells, on the hand, are cells that are less mature and more “primitive” or stem-cell like. Therefore, when Dr. Rui and colleagues added prolactin to the cells exposed to 3-ketosteroids, the expansion of CK5 cells was prevented.
In other words, 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,” says Dr. Rui, “the hormone can also drive other types of breast cancer, so we must proceed with caution. An alternative possibility supported by this research is inhibiting a protein called BCL6 that appears to be critical for steroid-induction of CK5 cells.” Dr. Rui adds, “Perhaps the simplest solution would be to seek alternatives to steroids for controlling the side-effects of chemotherapy in patients with this tumor subtype."
Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism C R Goodman, T Sato, A R Peck, M A Girondo, N Yang, C Liu, A F Yanac, A J Kovatich, J A Hooke, C D Shriver, E P Mitchell, T Hyslop and H Rui Oncogene advance online publication 22 June 2015; doi: 10.1038/onc.2015.193
_Illustration: Micrograph showing a lymph node invaded by ductal breast carcinoma, with extension of the tumour beyond the lymph node. Credit: Nephron/Wikipedia _