Why Do Some Breast Cancers Spread to the Brain?

Why do some breast cancers spread to the brain, called brain metastasis, while others stay in the breast area?

Scientists are starting to tease out some possible answers.

New research in cells and animal models suggests that certain mutations in the p53 gene, also called the TP53 gene, may be the reason.

“We found a correlation between the prevalence of p53 mutations [in the breast cancer tumor] and the likelihood of brain metastasis across the breast cancer molecular subtypes,” explained Uri Ben-David, PhD, professor in the Gray Faculty of Medical and Health Sciences at Tel Aviv University.

The p53 gene helps prevent cancer from developing by stopping cells with damaged DNA from multiplying.

The p53 gene and the p53 protein it creates also oversee the creation of fatty acids. Fatty acids are critical for healthy brain function because nearly 60% of the brain is fat.

The cellular environment in the brain is very different from the cellular environment of the breast. So how do breast cancer cells adapt to living in the brain?

“According to our findings, this adaptation is closely linked to the impairment of the p53 gene,” Ronit Satchi-Fainaro, PhD, said in a statement. In other words, a p53 gene mutation allows breast cancer cells to live in the brain. Satchi-Fainaro is professor and chair of the Department of Physiology and Pharmacology at Tel Aviv University.

The researchers found that cancer cells with a mutated p53 gene produce more fatty acids than normal cells. This allows them to grow and divide more rapidly in the brain. The cancer cells with the p53 mutation were able to make more fatty acids because they had higher levels of an enzyme called SCD1.

The researchers then used drugs to shut down the SCD1 enzyme in these cancer cells in the brain. This stopped the growth of the cancer cells, both in mice and in samples of breast cancer that had spread to the brain.

The researchers said these early results could one day lead to treatments specifically for breast cancer that has spread to the brain (brain metastases). The findings also may help doctors identify people with a high risk of developing brain metastases.

“In the future, the p53 status could be used to determine patients at higher risk of developing brain metastasis, which could affect disease monitoring — for example, head MRI — as well as selection of drugs (for example, which specific HER2 inhibitor to prescribe to a patient) based on the drugs' ability to penetrate the blood-brain barrier and target cells in the brain,” Ben-David said.