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The sneaky way oestrogen drives brain metastasis in non-oestrogen-dependent breast cancers

4 Mar 2019

Triple-negative breast cancers are more likely than other breast cancer types to metastasise and are especially likely to go the brain in younger women.

Researchers have tested various hypotheses to explain this danger.

One idea that has gotten little attention is the thought that oestrogen might be to blame.

After all, triple-negative breast cancers lack oestrogen receptors (along with progesterone receptors and HER2, thus the name triple negative) and so these cancers can't possibly be influenced by oestrogen.

A study published in the journal Oncogene has shown that while oestrogen does not directly affect triple-negative breast cancer cells, it can affect surrounding brain cells in ways that promote cancer cell migration and invasiveness.

Importantly, the study also suggests ways to stop the activity of oestrogen in the brain that fertilises triple-negative breast cancer metastasis.

"The cancer cells aren't responsive to oestrogen, but oestrogen influences the microenvironment. We found that astrocytes - one of the main components of the microenvironment in the brain - are oestrogen-responsive. When they are stimulated with oestrogen, they produce chemokines, growth factors, and other things that promote brain metastasis," explained Diana Cittelly, PhD, investigator at CU Cancer Center and assistant professor in the CU School of Medicine Department of Pathology.

Technically, the team found that oestrogen induces astrocytes (brain cells) to produce growth factors called brain-derived neurotrophic factor (BDNF) and Epidermal Growth Factor (EGF).

These factors activate two genetic migration/invasion switches in cancer cells, namely TRKB and EGFR.

"This may explain why breast cancers diagnosed in younger women are more likely to metastasise to the brain - pre-menopausal women have more oestrogen, and it may be influencing the microenvironment of the brain in ways that aid cancer," Cittelly said.

Traditionally, oestrogen-positive cancers have been treated with anti-oestrogen receptor therapies including tamoxifen.

However, it has always seemed obvious that cancers without oestrogen receptors would not respond to anti-oestrogen receptor therapy.

Unfortunately, there has been little opportunity to accidentally notice the effects of anti-oestrogen therapy on brain metastases resulting from breast cancer.

"Historically, women with brain metastases have been excluded from clinical trials due to overall poor prognosis," said Cittelly, who also pointed out that earning approval for a new drug requires showing its effectiveness, and even a promising drug may seem ineffective in patients whose cancer has already metastasised to the brain. "So we have never explored whether anti-oestrogens will have benefit for these women. Our work shows there might be a benefit in anti-oestrogen therapies in preventing brain metastasis in women with triple-negative breast cancer."

Additionally, Cittelly and colleagues recently received funding to explore interceding elsewhere in this chain of action that starts with oestrogen and ends with brain metastasis.

Basically, if oestrogen works through EGFR or TRKB, it may be useful to inhibit EGFR and/or TRKB, alone or together, in these patients.

Fortunately, like oestrogen-receptor inhibitors, EGFR and TRK inhibitors already exist and are in use with other cancers, which make the testing of these strategies dramatically more feasible.

"We are finally beginning to recognise the unique role of the microenvironment in the brain," Cittelly added. "Cancer metastasis may not depend on cancer cells alone. Stopping metastasis in these patients may require looking at the conditions of tissues that surround and support cancers."

Source: University of Colorado Anschutz Medical Campus