Does progesterone assist breast cancer cells evade the immune system?

The link between hormones and breast cancer growth has been known for many years and is led to the development of many therapies which have saved countless lives. Christie Hagan, Ph.D., an assistant professor at the University of Kansas has been studying progesterone and its relationship to the immune system. Progesterone is initially produced by the ovaries and plays an important role in a woman’s menstrual cycle, and pregnancies. Though progesterone declines after menopause it continues to be produced in the body’s fatty tissues including the breast and extremities. Even though hormone levels drop dramatically after menopause, most notably breast cancers in postmenopausal women are still driven by hormones.

Dr. Hagan’s research has led her to believe that breast tumor cells circulating in the body when exposed to progesterone may be concealed by this hormone to the tumor’s danger signals that are normally recognized by the immune system. Her work suggests that progesterone may help tumor cells go undetected. The question she asked is … “Can progesterone be blocked?” She notes that a constant signal of tumor cells can overstimulate our immune system. This results in the system’s ability to attack tumor cells becoming compromised. Dr. Hagan noted that some types of cancer such as skin cancer and lung cancer respond to drugs that reawaken the immune system such as immune checkpoint inhibitors. Aside from triple-negative breast cancers, many breast cancers are quote immune-cold” meaning that they don’t respond as well to immune attack and in particular this type of therapy. Dr. Hagan hypothesizes “that one reason breast tumors are immune-cold is that progesterone is Inhibiting the immune’s systems ability to do its job.” She has hypothesized that incorporating anti-progesterone may make breast tumors more receptive to immune checkpoint inhibitors. Dr. Hagan and her team are currently investigating their theory using animal models. She noted that they are excited about their data in her preclinical studies and furthermore noted that lots of studies have centered on estrogen and because of this, scientists have developed highly effective therapies as a result. She believes that her work on progesterone holds the same potential.

In a personal email conversation with Dr. Hagan, she added some thoughts on the mechanism of tumors being missed because of the presence of progesterone receptors. She believes that much of this is achieved through multiple mechanisms including that of MHC class I proteins ( group of genes that code for proteins found on the surfaces of cells that help the immune system recognize foreign substances.) (less antigen being expressed to the immune system), decreased recruitment of dendritic cells (fewer cells around to recognize antigen), and increase recruitment of regulatory T cells (more immune cells around to dampen the antitumor CD8 T cell response). In the same email conversation, I also asked her about natural (progesterone) versus synthetic progesterone (progestins) use in postmenopausal women. She said, “your second question is tougher because it requires distinguishing how progesterone modulates the immune system in such a way that allows tumors to be missed by the immune system. We think that PR -positive tumors achieve this through multiple mechanisms She of course reminded me of the clear link between exogenous progestins and breast cancer risk as shown in the Women’s Health Initiative trials of the early 2000s. She noted that currently, we don’t have good evidence to suggest that progesterone (the native hormone) increases breast cancer risk when taken by postmenopausal women. Trials of this very nature are ongoing in Europe now, the results of which will be quite interesting to see. In her final statement, she noted that “these progestins are messy, and have been shown to work through many different nuclear receptors, not just PR. So, the short answer, I can’t say right now what progesterone is doing in postmenopausal women, but it is of great interest to us.”

Dr. Alan Stolier, MD, FACS, clinical breast oncologist, shares his expert medical perspective with a series of educational and scientific articles.