A groundbreaking study from Harvard Medical School researchers should change long-held beliefs about the BRCA1 gene and its role in breast cancer. Researchers have discovered that even a single defective copy of the BRCA1 gene can make breast cells more susceptible to cancer, without the need for a second genetic “hit,” as previously thought. The findings, published in Nature Genetics, could change how doctors approach cancer prevention for individuals with a single BRCA1 mutation.
For years, scientists have adhered to the “two-hit” hypothesis to explain how BRCA1 mutations lead to cancer. According to this model, individuals who inherit one mutated copy of the BRCA1 gene typically were protected, as the second, normal copy of the gene would still aid in DNA repair. But if both BRCA1 copies—one inherited from each parent—were damaged, the DNA repair needed to avert cancer development wouldn’t occur.
However, the new study gets to the root of observations that even people with just one harmful BRCA1 mutation are more likely to develop cancer later in life.
“Our work provides an answer to what’s been a lingering question in the field. It shows why and how even a single defective copy of BRCA1 can alter cells in a way that accelerates cancer,” said Joan Brugge, PhD, senior author of the study, director of the Harvard Ludwig Cancer Center, and professor of cell biology at Harvard Medical School. “Our findings show that the two-hit hypothesis of cancer development offers only a partial explanation.”
This new study suggests that the presence of a just a single BRCA1 mutation primes breast cells to develop cancer in ways not previously understood.
The research could have significant implications for cancer prevention for women with inherited BRCA1 mutations who are at a higher risk for developing breast and ovarian cancers. Currently, preventive options for people with BRCA1 mutations are limited. Women may choose to undergo regular surveillance to detect tumors early, but this approach does not reduce the risk of cancer. Alternatively, they may opt for estrogen therapy, though its benefits remain unclear, or undergo prophylactic mastectomies—which reduce cancer risk by up to 95% but are invasive, costly, and life-altering.
“Our results clarify our understanding of how BRCA1-driven breast cancer arises and open up new possibilities for cancer prevention, such as therapies that target the cancer-fueling reprogramming that occurs inside the cell before tumors begin to form,” said study first author Carman Li, PhD, a postdoctoral researcher in the Brugge lab.
For their research, the investigators followed two group of mice to see if the two-hit model fully explains BRCA1-driven breast cancer. One group of mouse models had one faulty and one normal BRCA1 gene, while the second group had two normal copies of the gene. The researchers then selectively disabled the normal copy of BRCA1 in the first group and both normal copies of BRAC1 in the second group, leaving both sets of mice without the cancer-suppressing activity of BRCA1. The two-hit hypothesis would suggest in this instance that cancer would develop at similar rates in both group of mice. Instead, the Harvard team found that mice with one defective copy of BRCA1 developed mammary gland tumors about 20 weeks earlier than those that originally had two normal copies.
“This indicates that the two-hit hypothesis alone does not explain the earlier incidence of breast cancer in animals with a single defective copy,” Brugge said. “If it were, cancer would have developed at the same time in both groups of mice.”
The researchers concluded that the presence of the inherited BRCA1 mutation itself was sufficient to predispose cells to cancer, even without the loss of the second gene copy.
To determine why this is the case, the investigators compared the mammary glands of both groups of mice and found that the group with the single defective BRCA1 gene showed changes in the organization and packing of DNA that render certain cancer promoting genes more readily accessible. Notably, the cells showed alterations in structure and organization of chromatin, which helps package and maintain DNA in the nucleus of a cell.
Some of these changes resembled those seen in cells that were already cancerous. One example is the cells with a single defective BRCA1 gene showed chromatin changes that made the WNT10A gene—which plays a role in regulating cell division and growth—more prone to activation. Overactive WNT10A genes can lead to aberrant cell growth, which promotes cancer development.
These findings not only reshape our understanding of BRCA1-related breast cancer but also raise broader questions about cancer development in general. For instance, there are similar changes also found in other BRCA1-related cancers such as ovarian cancer and might be similar alterations occur cancers driven by other genes linked to cancer.
“We are excited to address these questions in the future,” said Li.
