Estrogen on the Brain: How Hormones Might Be Increasing Brain Metastasis

Reading time: 3 minutes

Sara Musetti

One of the realities of cancer is that the primary tumor is rarely the cause of issues; usually, mortality and complications come from tumor cells spreading throughout the body and forming new tumors, a process called metastasis. For most cancers, the primary tumor can be surgically removed, but once tumor cells have made their way into the blood or lymph nodes, it becomes much harder to effectively treat the resulting tumors. Unfortunately, we often don’t understand exactly how tumors metastasize, especially because no two tumors are the same. However, recent work on triple negative breast cancer (TNBC) indicates that for some patients, hormones may play a role.

Triple negative breast cancer is especially common in young women and is especially deadly; triple negative breast cancer metastasizes rapidly and often finds its way to the brain. Interestingly, premenopausal women are twice as likely to develop brain metastases as post-menopausal women. For this reason, researchers at the University of Colorado Denver began investigating whether hormones in the estrogen family, which are produced more heavily in premenopausal women, might be responsible for this trend. They recently published that estradiol (also known as E2), an important member of the estrogen family, is capable of stimulating the production of brain-derived neurotropic factor (BDNF), which stimulates growth and invasion in cancer cells.

To further study the effect of estrogen on cancer, researchers took mice that were estrogen-deficient and exposed them to TNBC cells. Some of these mice were also given estradiol. Mice exposed to both estradiol and TNBC cells had four times as many brain metastases, on average, than mice who were exposed to TNBC cells without the presence of estradiol. Estradiol treatment also lead to far poorer rates of survival compared to those without. However, the researchers knew that estradiol was not working directly on the cancer cells, as one of the defining characteristics of TNBC is a lack of estrogen receptors (“triple negative” refers to a lack of estrogen receptors, progesterone receptors, and HER2 growth receptors). So how is estradiol influencing metastasis?

How estrogen conditions the brain for metastases. (1) Estrogen in the blood stream crosses into the brain and is taken up by astrocytes. (2) Astrocytes, stimulated by estrogen, produce BDNF. (3) Circulating tumor cells in the bloodstream sense BDNF and cross the blood-brain barrier, forming metastases.

It turns out the estrogen is actually acting on brain cells called astrocytes that express estrogen receptors. Estrodiol activates the production of BDNF, a growth factor, in astrocytes, which then attracts and stimulates the invasion of BDNF-sensing TNBC cells in the blood.

This is a paradigm shift for how clinicians think about and treat TNBC. For example, this team tested whether tamoxifen, a cancer drug used for estrogen receptor positive cancers that works by blocking estrogen uptake by those cancer cells, can impact metastasis.They found that tamoxifen, which is not effective at treating TNBC primary tumors, can help prevent the formation of brain metastases. This is great news; if the same trend holds in humans, then a drug that is already widely used can be made available to TNBC patients to protect them from brain metastases while their primary tumor is treated. It is also worth examining whether this mechanism is also present in other tissues, such as the lungs, that are also common sites of breast cancer metastasis.

Tamoxifen: © wikipedia

Works Discussed:

Contreras-Zárate, M. J., Day, N. L., Ormond, D. R., Borges, V. F., Tobet, S., Gril, B., Steeg, P.S., Cittelly, D. M. (2019). Estradiol induces BDNF/TrkB signaling in triple-negative breast cancer to promote brain metastases. Oncogene, 1.

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