Estrogen May Trigger Brain Metastasis in Triple-negative Breast Cancer, Study Shows

Estradiol, a type of estrogen and the major female hormone, may drive the spread of cancer to the brain in women with triple-negative breast cancer (TNBC), a study in mice and human cells reports.

Researchers identified a chain of molecular events triggered by estradiol that appears to be behind tumor cells’ ability to form brain metastases. This process involves increased production of a brain-specific protein called BDNF and the activation of its receptor molecule, TrkB, in tumor cells.

This discovery may have important therapeutic implications, since it provides a basis to use estradiol-depletion treatments or inhibitors that target this pathway to prevent or delay the spread of TNBC to the brain.

The study, “Estradiol induces BDNF/TrkB signaling in triple-negative breast cancer to promote brain metastases,“ was published in the journal Oncogene.

TNBC is more likely than other types of breast cancer to spread to other parts of the body, that is, to metastasize. It is particularly likely to invade the brain in younger women. But scientists aren’t sure why yet.

Now, work led by postdoctoral researcher María Contreras-Zárate, PhD, and investigator Diana Cittelly, PhD, at the University of Colorado Cancer Center suggests that a mechanism that was previously viewed as unlikely might actually be the key.

Because triple-negative breast cancers lack the receptors for estrogen (as well as progesterone receptors and HER2), they are not expected to be affected by this hormone.

However, the researchers proved that, although cancer cells are not directly responsive to estrogen, the hormone can stimulate important brain cells called astrocytes to release factors (chemokines, growth factors, etc.) that promote brain metastases.

When mouse models of TNBC-derived brain metastasis were treated with estradiol, the number of cancer cell clusters in the brain significantly increased.

Estradiol induced the production of a factor called brain-derived neurotrophic factor (BDNF) in human astrocytes cultured in the lab or in the brains of mice, the researchers noted.

On the other hand, a receptor for this factor, a molecule called tropomyosin kinase receptor B (TrkB), was overproduced in different human TNBC cell lines with increased propensity to form brain metastases and in transplants of human brain metastasis in mice.

These results establish a link between estradiol and a tumor’s potential to invade the brain. Estradiol triggers an increased production of BDNF in brain astrocytes. In turn, this activates TrkB in cancer cells, turning on cellular pathways that make those cancer cells more prone to migrate and invade tissues, giving rise to metastases.

Based on these findings, the researchers reasoned that a therapy that blocks this process at some point could prevent the formation of brain metastasis.

In fact, when mice stimulated with estradiol were given a BDNF/TrkB inhibitor, the number of brain metastatic clusters dropped significantly.

“These findings have important therapeutic implications, as they provide a rationale to use E2-depletion therapies or TrkB inhibitors to prevent or delay development of BM [brain metastasis] in younger women.”

“This may explain why breast cancers diagnosed in younger women are more likely to metastasize to the brain — pre-menopausal women have more estrogen, and it may be influencing the microenvironment of the brain in ways that aid cancer,” Cittelly said in a University of Colorado news story by Garth Sundem.

“Historically, women with brain mets have been excluded from clinical trials due to overall poor prognosis,” she added. “So we have never explored whether anti-estrogens will have benefit for these women. Our work shows there might be a benefit in anti-estrogen therapies in preventing brain metastasis in women with triple-negative breast cancer.”

Cittelly and her colleagues recently received funding to explore the therapeutic potential of inhibitors targeting the estradiol pathway.

Some of these therapies (e.g., EGFR and TRK inhibitors) already exist and are used for other cancers, making them easier to be tested.