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Breakthrough offers hope for treating breast cancer that spreads to the brain

Israeli scientists have uncovered, for the first time, how breast cancer cells adapt to and survive in the brain, TPS-IL reported citing the Tel Aviv University. The discovery could pave the way for new treatments, improved risk prediction, and earlier intervention for brain metastases — a highly lethal condition for which no effective targeted therapy currently exists.

The findings come from a large-scale international study led by scientists at the Gray Faculty of Medical and Health Sciences at Tel Aviv University, in collaboration with 14 laboratories across six countries. The research — led by Prof. Uri Ben-David and Prof. Ronit Satchi-Fainaro, together with Dr. Kathrin Laue and Dr. Sabina Pozzi — addresses a long-standing mystery in oncology: why certain breast tumors preferentially metastasize to the brain.

The study was published in the peer-reviewed Nature Genetics.

“Most cancer-related deaths are not caused by the primary tumor but by its metastases to vital organs,” Prof. Satchi-Fainaro said. “Among these, brain metastases are some of the deadliest and most difficult to treat. One of the key unresolved questions in cancer research is why certain tumors metastasize to specific organs and not others.”

Among people with metastatic breast cancer, about 10%–15% develop brain metastases during the course of their illness, according to Breastcancer.org, a nonprofit site offering expert-reviewed information and support on breast cancer.

While the tumor suppressor gene p53 has long been associated with aggressive cancer, the study reveals a previously unknown, brain-specific role for the gene. The researchers identified a distinct chromosomal alteration — the loss of the short arm of chromosome 17 — that strongly predicts the later development of brain metastases in breast cancer patients. This deletion results in the loss of functional p53.

“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. Ben-David said. “The reason for this is the loss of an important gene located on this arm. This gene is p53, often referred to as ‘the guardian of the genome.’”

Crucially, the researchers found that p53 loss does not simply make cancer cells more aggressive overall. Instead, it enables a specific metabolic adaptation that allows breast cancer cells to survive and proliferate in the brain, an environment fundamentally different from the breast tissue where the primary tumor originates.

“The brain’s environment is fundamentally different from that of the breast,” Prof. Satchi-Fainaro said. “The question is how a breast cancer cell, adapted to its original environment, can adjust to this foreign one.”

According to the study, p53 normally regulates fatty acid synthesis, a metabolic pathway particularly important in brain tissue. When p53 is impaired or absent, cancer cells dramatically increase fatty acid production, giving them a growth advantage in the brain. In experiments, breast cancer cells lacking functional p53 proliferated far more aggressively when introduced into the brains of mice than cells with intact p53.

The team also uncovered a previously unrecognized interaction between cancer cells and astrocytes, support cells in the brain that normally secrete substances to nourish neurons. In the absence of p53, cancer cells intensify their interaction with astrocytes and hijack these secreted substances, using them as raw materials for fatty acid synthesis.

A central player in this process is the enzyme SCD1, which plays a key role in fatty acid production. The researchers found that SCD1 expression and activity were significantly higher in cancer cells with impaired or missing p53, making the enzyme a critical vulnerability.

“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. Ben-David said.

The researchers tested several drugs that inhibit SCD1, some already under development for other diseases. “We found that SCD1 inhibition in brain metastatic cells with impaired p53 was effective and significantly hindered the development and proliferation of cancerous metastases,” Ben-David said. The effect was observed both in mouse models and in samples taken from brain metastases of women with breast cancer.

Doctors could use the study’s findings to identify breast cancer patients at higher risk of brain metastases before the cancer spreads. By testing tumors for p53 mutations or deletion of part of chromosome 17, clinicians could tailor monitoring, such as more frequent brain MRIs, while sparing low-risk patients from unnecessary imaging or aggressive treatments.

The research also points to a potential treatment by targeting SCD1, an enzyme essential for fatty acid production in cancer cells lacking p53. Drugs that inhibit SCD1, some already in development, were shown to slow the growth of brain metastatic cells in lab and animal models, offering hope for the first effective therapy against breast cancer brain metastases.

“We identified several characteristics of cancer cells causally linked to this deadly phenomenon,” the researchers concluded. “While the road ahead is still long, the potential is immense.”