(Image caption: The images show an early developmental stage of normal (top row) and BRCA1-deficient brains (bottom row). The imaged embryos show abundant proliferation of cell growth (red, first column) in both normal and BRCA1-deficient brains at this stage. However brains lacking BRCA1 exhibit high levels of cellular suicide (green, second column). The third column shows an overlay of the other columns. Credit: Courtesy of the Salk Institute for Biological Studies)

Scientists reveal potential link between brain development and breast cancer gene

Scientists at the Salk Institute have uncovered details into a surprising—and crucial—link between brain development and a gene whose mutation is tied to breast and ovarian cancer. Aside from better understanding neurological damage associated in a small percentage of people susceptible to breast cancers, the new work also helps to better understand the evolution of the brain.

The research, published this month in PNAS, shows that the gene known as BRCA1 has a significant role in creating healthy brains in mice and may provide a hint as to why some women genetically prone to breast cancer experience brain seizures.

"Previously, people associated mutations or deletions of BRCA1 with breast and ovarian cancer," says Inder Verma, a professor in Salk’s Laboratory of Genetics and American Cancer Society Professor of Molecular Biology. "Our paper goes beyond this link to explain the protective mechanism of BRCA1 in the brain."

Through a three–lab collaboration at the Salk Institute, which began over a water cooler conversation between adjacent lab researchers 10 years ago, the work has culminated in dramatic findings. The team found that eliminating BRCA1 in neural stems cells had profound effects: large swaths of brain were simply missing; the cortex, which typically has six layers, only developed two very rudimentary layers; the cerebellum, which is normally made up of many folds and creases, was almost completely smooth; and the olfactory bulb, which processes odor information, was severely disorganized and poorly developed. Neurons were dying rapidly shortly after forming, while ones that did last were often defective. In mouse models, this resulted in interference in balance, motor skills, and other core functions.

How exactly was the absence of BRCA1 leading to such a neural catastrophe? In a previous paper, the team showed that without the protein coded by the BRCA1 gene, DNA is not packaged properly, becoming fragile and more likely to break during DNA replication. In this new paper, the researchers reveal more about that mechanism, showing that without the protective ability of BRCA1, breaks in the DNA strands go unfixed, prompting the molecule ATM kinase to activate a cellular “suicide” pathway involving a protein called p53. This pathway helps to halt the replication of damaged cells and is important in cancer research.

"BRCA1 acts by conferring stability to the DNA and preventing it from breaking," says Carlos G. Perez–Garcia, a Salk researcher in the Molecular Neurobiology Lab. "BRCA1 is important for all healthy cells."

When the researchers eliminated both BRCA1 and p53, they found the neurons grew at a normal rate, but still disorderly, with cells pointed in the wrong direction.

"In this scenario, we recover a lot of neurons but there’s still a lot of abnormalities, such as cells that are sideways and pointed the wrong direction," says Gerald Pao, who, along with Quan Zhu and Perez–Garcia, is a primary contributor to the paper and Salk researcher.

This observation led the team to propose that BRCA1 has an additional role in assisting neurons in orienting: the gene acts on the centromere of DNA—essentially an anchor for the chromosome arms essential in cell replication—to tell the new cell in which direction to grow, providing guidance in developing the brain’s organized layers.

"It is remarkable that BRCA1 has such a significant effect on the brain, especially size. This work leads us to a better understanding of how to protect neurons," says Verma, who is also the Irwin and Joan Jacobs Chair in Exemplary Life Science. Because BRCA1 seems to regulate the centromere, studying the gene will help scientists to understand how mammalian brains have evolved over time.

"Now we have an explanation for why some patients with breast cancer also experienced brain seizures," adds Pao. This knowledge could potentially help identify breast cancer–susceptible patients predisposed to seizures and provide appropriate treatments.

Breast cancer spreads to brain by masquerading as neurons

Often, several years can pass between the time a breast cancer patient successfully goes into remission and a related brain tumor develops. During that time, the breast cancer cells somehow hide, escaping detection as they grow and develop. Now City of Hope researchers have found out how.

Breast cancer cells disguise themselves as neurons,  becoming “cellular chameleons,” the scientists found. This allows them to slip undetected into the brain and, from there, develop into tumors.

The discovery is being heralded as “a tremendous advance in breast cancer research.”

Although breast cancer is a very curable disease – with more than 95 percent of women with early-stage disease surviving after five years – breast cancer that metastasizes to the brain is difficult to fight. In fact, only about 20 percent of patients survive a year after diagnosis.

"There remains a paucity of public awareness about cancer’s relentless endgame," said Rahul Jandial, M.D., Ph.D., a City of Hope neurosurgeon who headed the breast-cancer-and-brain-tumor study, published online ahead of print this week in the Proceedings of the National Academy of Sciences.

"Cancer kills by spreading. In fact, 90 percent of all cancer mortality is from metastasis," Jandial said. "The most dreaded location for cancer to spread is the brain. As we have become better at keeping cancer at bay with drugs such as Herceptin, women are fortunately living longer. In this hard-fought life extension, brain metastases are being unmasked as the next battleground for extending the lives of women with breast cancer."

He added: “I have personally seen my neurosurgery clinic undergo a sharp rise in women with brain metastases years – and even decades – after their initial diagnosis.”

Jandial and other City of Hope scientists wanted to explore how breast cancer cells cross the blood-brain barrier – a separation of the blood circulating in the body from fluid in the brain – without being destroyed by the immune system.

“If, by chance, a malignant breast cancer cell swimming in the bloodstream crossed into the brain, how would it survive in a completely new, foreign habitat?” said Jandial in a recent interview with New Scientist.

Jandial and his team’s hypothesis: Given that the brain is rich in many brain-specific types of chemicals and proteins, perhaps breast cancer cells that could exploit these resources by assuming similar properties would be the most likely to flourish. These cancer cells could deceive the immune system by blending in with the neurons, neurotransmitters, other types of proteins, cells and chemicals.

Taking samples from brain tumors resulting from breast cancer, Jandial and his team found that the breast cancer cells were exploiting the brain’s most abundant chemical as a fuel source. This chemical, GABA, is a neurotransmitter used for communication between neurons.

When compared to cells from nonmetastatic breast cancer, the metastasized cells expressed a receptor for GABA, as well as for a protein that draws the transmitter into cells. This allowed the cancer cells to essentially masquerade as neurons.”Breast cancer cells can be cellular chameleons (or masquerade as neurons) and spread to the brain,” Jandial said.

Jandial says that further study is required to better understand the mechanisms that allow the cancer cells to achieve this disguise. He hopes that ultimately, unmasking these disguised invaders will result in new therapies.