Why Is the Brain Such a Desirable Target for Breast Cancer?

Breast cancer is the most common malignancy among women, and its brain metastases carry the most unpredictable and often fatal outcomes. The challenge of treating this particular metastasis lies not only in the need to cross the blood-brain barrier to deliver drugs: until recently, scientists did not even understand the mechanism by which cancer cells migrate from breast tissue to the brain, nor why cancer cells target it in the first place given that the microenvironment differs significantly. It is precisely these metastatic mechanisms that researchers publishing in Nature Genetics set out to investigate.

The scientists began by analyzing the DNA of tumor cells from 1,756 women with breast cancer, finding that patients who subsequently developed brain metastases frequently carried mutations in the TP53 gene. This gene encodes the p53 protein, which suppresses the proliferation of cells with damaged DNA and triggers their death, acting as one of the cell's fundamental safeguards against malignant transformation.

In data analysis, the researchers took a unique step that ultimately revealed p53's role in metastasis: rather than only examining point mutations in TP53, they also accounted for deletions of the short arm of the chromosome carrying it. When all forms of TP53 inactivation were considered, it turned out that in 100% of cases, the affected cells went on to produce brain metastases.

"When all forms of TP53 inactivation were considered, (...) in 100% of cases, the affected cells went on to produce brain metastases"

The team then set out to test whether the loss of this single gene was truly sufficient to drive metastasis specifically to the brain. They modeled systemic metastasis in two groups of mice — one group received cancer cells with functional p53, the other received cells lacking it. The researchers then assessed the extent of metastasis across various organs in both groups and found that disabling p53 enabled cancer cells to establish themselves specifically in the brain, while tumors barely developed in other organs. When both cell types were introduced simultaneously into the same animal, the outcome was consistent: cells without p53 almost invariably found their way to the brain. Notably, this p53-loss mechanism of brain metastasis was not exclusive to breast cancer, but was also seen in carcinoma, a cancer of epithelial cells.

Yet one question remains unanswered: why is the brain such an appealing destination for these cells? In essence, the space within the skull is almost entirely occupied by neurons and glial cells, leaving virtually no standing reserve of nutrients. For this reason, some nutrients are shuttled from blood vessels to neurons by specialized glial cells called astrocytes, while others are synthesized by astrocytes directly for the neurons' use. And it is within those very astrocytes that the root of the problem lies.

It turns out that p53 also suppresses an active fatty acid synthesis pathway. When p53 is inactivated, cancer cells begin overproducing fatty acids, using them to construct membranes for themselves and new daughter cells, as well as to buffer against cellular stress. When such cancer cells enter the brain, the first to detect them are the astrocytes. These cells shift from their resting state into an activated, or reactive, state. In an attempt to protect the brain from foreign and pathological invaders, astrocytes enlarge and begin secreting… fatty acids. Under ordinary circumstances, this response genuinely helps arrest the spread of foreign cells — but in the case of breast cancer, it creates a vicious cycle. Astrocytes release fatty acids as a defense measure → cancer cells exploit them for growth and propagation throughout the brain → an increasing number of astrocytes joins the defensive response→ producing yet more fatty acids for the cancer cells to consume.

"When the [SCD1] inhibitor was tested (...), it not only slowed tumour growth but also contributed to cancer cell death."

The key enzyme driving this newly identified fatty acid synthesis chain in cancer cells is SCD1. The researchers decided to test whether inhibiting this enzyme could halt tumor spread. They administered an SCD1 inhibitor to mice bearing breast cancer brain metastases, and just ten days later, MRI imaging revealed a significant reduction in the volume of p53-deficient tumors. The results in human tissue were equally encouraging: when the inhibitor was tested on cultured cancer cells and neurons derived from deceased donors, it not only slowed tumor growth but also contributed substantially to cancer cell death. 

The researchers' greatest hope is that a clinical therapy targeting brain metastases from breast cancer could reach patients within the next few years. Because SCD1 inhibitors are already in clinical use for other conditions, the path through the FDA approval process may be considerably shorter than for a wholly novel compound. More than a molecular discovery, this research reframes a disease that has long resisted treatment at its most devastating stage, offering more than two million women diagnosed with breast cancer each year a scientific foundation for real, near-term hope.

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This article was written by Renata Tulakina and edited by Julia Dabrowska, with graphics produced by Lilly Green. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.