The breast cancer type 1 (BRCA1) gene carries a lot of medical clout. Mutations in the tumor suppressor gene markedly increase risk for certain cancers, particularly in the breast (1). Often, people who find out that they carry certain BRCA1 mutations decide to get preventative mastectomies, where the entire breast is removed to reduce cancer risk.
Joan Brugge, a biologist at Harvard Medical School, has built a career on figuring out how certain proteins gone rogue could lead to cancer. Her lab hadn’t really studied BRCA1 before — until an individual with a family history of inherited BRCA1 mutations came to her with some seed money for a new project.
Brugge and her team were curious about how exactly BRCA1 mutations caused cells to become cancerous. The main theory, called the two-hit hypothesis, said that it took two mutations — one in each allele of the gene — to cause cancer development in the cell (2). In work recently published in Nature Genetics, the scientists have now found that one mutated BRCA1 allele is all it takes to push the cell towards cancer growth through changes in the cell’s epigenome (3). These findings, the scientists say, could lead to new strategies to both diagnose and treat breast cancer.
The first step toward understanding how BRCA1 mutations led to cancer development was to generate a mouse model that could recapitulate how human breast cancer occurs. Breast cancer can often develop when people born with one BRCA1 mutation develop a second mutation later in life. To mimic this, the scientists developed two mouse lines: A heterozygous mouse with one mutated and one functional BRCA1 allele, and a wild type mouse with two functional BRCA1 alleles.
Because these mice were genetically engineered, the team could inactivate the remaining BRCA1 allele in the heterozygous mouse and the two BRCA1 alleles in the wild type mouse by injecting a lentivirus into the mouse’s mammary cells. This virus inactivated the transformation related protein 53 (Trp53) gene that is commonly mutated with BRCA1 in breast cancer.
The animals then developed breast tumors, similarly to how humans do. “It kind of resembled the sporadic loss that you would see in BRCA carriers, where there’s just going to be a random mutation that causes the loss of the second copy,” said Brugge.
The heterozygous mice were still faster in developing tumors. It suggests that the two-hit hypothesis is not wrong but is not enough to fully explain this cancer predisposition.
- Carman Man-Chung Li, Harvard Medical School
The researchers next decided to test if the two-hit hypothesis held up. According to this hypothesis, if they inactivated the remaining BRCA1 allele in the heterozygous mouse and the two BRCA1 alleles in the wild type mouse simultaneously, tumor formation would happen at the same time in both mouse models. “But what we saw was actually not that,” said Carman Man-Chung Li, a postdoctoral scholar in Brugge’s lab and one of the study’s authors. “The heterozygous mice were still faster in developing tumors. It suggests that the two-hit hypothesis is not wrong but is not enough to fully explain this cancer predisposition.”
To find the missing pieces of this mystery, the scientists looked at the chromatin from the heterozygous and wild type mice before tumor formation. They found that much of the heterozygous cells’ chromatin looked more like cancer cells than normal cells. These chromatin changes allowed certain tumor-promoting genes to be more easily turned on in heterozygous cells than in wild type cells. This indicated that the heterozygous cells, with only one BRCA1 mutation, had an epigenome that potentially predisposed the cell to developing cancer.
This new finding might lead to more targeted therapies for BRCA1-associated cancers, said Mary Daly, a cancer biologist at the Fox Chase Cancer Center. “Maybe we can find something that would inhibit these factors that cause chromatin instability or chromatin changes,” she added.
Before that, though, Daly noted that it remains to be seen whether these epigenomic changes also occur in humans. “There’s a lot of heterogeneity in patients,” said Li. “Now, we’re trying to figure out what’s going [on] with humans, but that requires a lot more samples.”
Brugge hopes that sequencing data from a consortium of women, including those with BRCA1 inherited mutations, could help answer these questions. “That should be feasible to see whether, in fact, you see these same differences,” she said. “If so, then you can really think about figuring out whether you could intercept the cancer development through modification of the program.”
References
- Fackenthal, J.D. & Olopade, O.I. Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer 7, 937–948 (2007).
- Chial, H. Tumor Suppressor (TS) Genes and the Two-Hit Hypothesis. Nat Edu 1, 177 (2008).
- Li, C.M.-C. et al. Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer. Nat Genet 56, 2763–2775 (2024).
