When breast cancer reaches the brain, treatment becomes much harder, and options narrow quickly. Triple-negative breast cancer (TNBC), an aggressive form that lacks three common markers used to guide treatment, is especially prone to making that trip.
But getting there is only part of the problem. Cancer cells also have to find a way to survive once they arrive.
Researchers at Wake Forest University School of Medicine may have identified one protein helping with both jobs. SIRPα is best known for regulating immune cells, yet the new work suggests it may also act inside TNBC cells, making them more mobile while changing the brain environment around them.
The study, published August 31 in Neuro-Oncology, is preclinical, meaning the treatment-related findings come from lab and animal experiments rather than patients. Still, the researchers found several clues that make SIRPα difficult to ignore.
The Protein Kept Showing Up Where The Cancer Spread
Human tumor data first pointed the team toward SIRPα.
When researchers examined human breast cancer data and tumor samples, SIRPα stood out. Levels were higher in TNBC cells, particularly in tumors that had spread to the brain, and higher levels were linked to poorer outcomes among TNBC patients. Cancer cells that tend to travel to the brain also produced more SIRPα than their parent cells.
David Soto-Pantoja, an associate professor of cancer biology at Wake Forest, led the study, with Yu-Ting Tsai as first author. Its plain-language summary says 35% of TNBC patients develop brain metastasis, although it does not specify which patients or the period over which that figure applies.
Finding more of a protein in aggressive tumors, however, does not prove the protein is driving the behavior. So the team moved from observation to mechanism, asking what SIRPα was actually doing inside the cells.
Related: Six simple health checks that can reveal important warning signs early
Cells Get Restless While The Brain’s Defenders Back Down
SIRPα seems to work both sides of the fight at once.
Inside cancer cells with high SIRPα levels, mitochondria broke into smaller pieces through a process called fission. That change involved a signaling chain known as SHP2/Erk/Drp1, and the affected cells became more mobile and more likely to spread in the study models.
When the researchers inhibited SIRPα in mice, metastasis rose throughout the body, not just in the brain.
But the cancer cells were only half of the story. SIRPα also increased fibronectin production, a protein in the structural scaffolding around cells. With repeated exposure to it, microglia, the immune cells that help defend the brain, stopped producing the same strong inflammatory and anticancer responses.
Soto-Pantoja put the two effects together: “Our findings suggest that SIRPα helps make tumor cells more aggressive while also changing the brain environment in ways that help those cells survive.”
Importantly, the study does not say a patient’s entire immune system shuts down. The weaker response described here involves the brain’s own immune cells.
Breast Cancer Cells Have Adapted To The Brain Before
Save this article
Enter your email address and we'll send it straight to your inbox.
Earlier research suggests SIRPα is one piece of a bigger pattern.
The idea that metastatic breast cancer cells adapt to the brain is not new. A 2014 study found that breast cancer cells that had reached the brain produced more of the proteins involved in handling GABA, a neurotransmitter, and used that machinery to support their growth.
A 2021 review in the British Journal of Cancer described a similar theme, noting that metastatic cells can pick up brain-like characteristics, including a GABA-related profile resembling that of resident neurons.
The same review described communication between cancer cells and astrocytes, another type of brain cell, in ways that can promote tumor growth and resistance to treatment.
That research is separate from the Wake Forest study. Still, it provides useful context: cells arriving in the brain may not simply survive there unchanged. They can adapt to their environment while influencing it in return. SIRPα may be another part of that exchange.
Why A Good Target Still Has A Long Road
Two obstacles sit between a lab finding and a treatment: who gets studied and whether a drug can reach the tumor.
One problem is trial access. A 2021 JAMA Oncology analysis examined 223 phase 3 trials involving metastatic breast cancer, lung cancer and melanoma. Of those, 52 excluded patients with brain metastases outright, while 124 allowed them only under certain conditions.
Those numbers cover three cancers rather than TNBC alone, and they represent a 2021 snapshot. Then there is the physical challenge of reaching the brain. The blood-brain barrier helps protect brain tissue, but it can also complicate treatment. The researchers want to explore whether blocking it could make existing immunotherapies or other treatments more effective against TNBC brain metastases.
Trial rules have often kept patients with brain metastases out of the studies that might help them. What would a fairer approach look like to you?
More Articles You Might Be Interested in:
- Why “Push Through It” Is the Worst Advice a Tired Woman Ever Got
- A study of 100,000+ women found a surprising breast cancer link with GLP-1 drugs
- Research Links This Common Mindless Habit to Higher Cancer Risk And You Might Be Doing It Daily
