HMS Study Reveals How Mutation Can Accelerate Breast Cancer Progression

A study led by Harvard Medical School researchers shed new light on how even a single defective copy of the tumor-suppressor BRCA1 gene can increase patients’ risk of developing breast cancer.

Scientists have long known that a single BRCA1 mutation is enough to significantly increase a patient’s chances of developing cancer, even among women who also inherit one normal copy of the gene. The new HMS study, published on Nov. 11 in “Nature Genetics,” suggests an explanation.

Previously, researchers knew that women born with one normal BRCA1 copy were more vulnerable to breast cancer because their second copy of the gene could later develop a mutation, while women with two normal BRCA1 copies had an extra layer of protection — an explanation known as the two-hit hypothesis.

But the new study found that cells with a single defective BRCA1 copy also have changes in the structure of chromatin, DNA-and-protein fibers that help package genetic information into chromosomes. Those changes then render the cell more vulnerable to tumor growth. The WNT10A gene — which helps control cell division and growth — becomes more active, allowing tumors to grow faster.

The research team followed two groups of mice: one with two normal copies of the BRCA1 gene, and the other with only one normal BRCA1 copy and one copy that was inherited with a mutation. When the researchers turned off the normal copies in both groups, the mice that originally had one defective BRCA1 gene developed mammary gland tumors about 20 weeks earlier than the other group that initially had two normal copies.

Researchers said if the two-hit hypothesis was the only explanation of increased breast cancer risk among patients born with only one normal BRCA1 copy, the study would have expected both groups of mice to develop tumors at the same time. But the difference they observed led the researchers to examine what other factors could predispose women with one defective BRCA1 copy to breast cancer.

HMS professor Joan S. Brugge, a co-author on the study and director of the Harvard Ludwig Cancer Center, said the study “adds a whole new dimension to our thinking about the nature of the alterations associated with inheriting a mutant copy of the BRCA1.”

While the molecular mechanism behind why losing one BRCA1 gene leads to chromatin changes remains unknown, the study helps provide a focal point for researchers moving forward.

“At least one can try to track it backwards,” Brugge said. “If you know what kind of alterations there are, you can try to figure out how one copy of BRCA1 is affecting that.”

Carman Man-Chung Li, a postdoctoral researcher and co-author on the paper, said she hopes the study will spark research on other cases of gene haploinsufficiency — a condition where the loss of even one copy of a gene prevents the normal expression of a protein, resulting in disease.

“It inspires the question of: How widely is this phenomenon being observed, and are there other effects of gene haploinsufficiencies that we didn’t know about that we can now discover because of this mouse model?” Li said.

Li said she was excited about the potential for translating research findings into practical tools that could improve techniques for cancer prevention and treatment. For instance, she said, understanding the chromatin changes that increase breast cancer risk in women with one defective BRCA1 copy might help researchers understand the development of ovarian cancer, which is also associated with BRCA1 mutations.

“Can we leverage these observations and turn them into something that can be applied to patients for early detection or early intervention?” Li said.