Breakthrough in Understanding Breast Cancer Metastasis to the Brain

Israeli scientists from Tel Aviv University have made a significant discovery regarding breast cancer cells and their ability to metastasize to the brain. This research, led by Professors Uri Ben-David and Ronit Satchi-Fainaro, along with Dr. Kathrin Laue and Dr. Sabina Pozzi, involved collaboration with 14 laboratories across six countries and was published in the peer-reviewed journal *Nature Genetics*. The study addresses a critical question in oncology: why certain breast tumors preferentially spread to the brain, a condition known for its high lethality and lack of effective targeted therapies.

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The researchers identified a specific chromosomal alteration—the loss of the short arm of chromosome 17—that is strongly associated with the development of brain metastases in breast cancer patients. This alteration leads to the loss of the tumor suppressor gene p53, which has been traditionally linked to aggressive cancer behavior. However, the study reveals that the loss of p53 specifically enables breast cancer cells to adapt metabolically to the brain's unique environment, enhancing their survival and proliferation.

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The study highlights that p53 normally regulates fatty acid synthesis, a crucial metabolic pathway in brain tissue. When p53 is absent, breast cancer cells significantly increase fatty acid production, which provides them with a growth advantage in the brain. Experiments demonstrated that cancer cells lacking functional p53 proliferated more aggressively in mouse brains compared to those with intact p53. Additionally, the research uncovered a novel interaction between cancer cells and astrocytes, the brain's support cells, which the cancer cells exploit for resources necessary for fatty acid synthesis.

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A central player in the survival of these cancer cells is the enzyme SCD1, which is involved in fatty acid production. The study found that SCD1 expression was markedly higher in cancer cells with impaired p53, indicating it as a critical vulnerability. The researchers tested several drugs that inhibit SCD1, some of which are already in development for other diseases. The results showed that SCD1 inhibition effectively slowed the growth of brain metastatic cells in both laboratory and animal models, suggesting a promising avenue for developing targeted therapies against breast cancer brain metastases.

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This research not only enhances the understanding of how breast cancer cells adapt to the brain but also opens up potential pathways for early intervention and treatment. By identifying patients at higher risk for brain metastases based on the presence of specific chromosomal alterations, healthcare providers may be able to implement preventative strategies. The findings also suggest that targeting SCD1 could lead to the first effective therapy for brain metastases in breast cancer, offering hope for improved patient outcomes.

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“Most cancer-related deaths are not caused by the primary tumor but by its metastases to vital organs,” — Prof. Ronit Satchi-Fainaro, Tel Aviv University

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“We found that when chromosome 17 in a cancer cell loses a copy of its short arm, the chances of the cell sending metastases to the brain greatly increase,” — Prof. Uri Ben-David, Tel Aviv University

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“Once we identified the mechanism and its key players, we sought to use the findings to search for a potential drug for brain metastases,” — Prof. Uri Ben-David, Tel Aviv University

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“The brain’s environment is fundamentally different from that of the breast,” — Prof. Ronit Satchi-Fainaro, Tel Aviv University

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