Research News

People who inherit BRCA mutations face an increased risk of developing breast cancer, but not every carrier will develop the disease. Understanding why some individuals develop cancer while others remain cancer-free is an important challenge in hereditary cancer research. New research from the Cleveland Clinic laboratory of Mihriban Karaayvaz, PhD, is helping scientists investigate what happens in breast cells with BRCA2 mutations long before cancer becomes detectable.

The study, published in iScience, found that a protein called DNA polymerase iota (Pol ι), helps BRCA2-deficient breast cells adapt to cancer-associated stress caused by a BRCA2 mutation. The paper also reports increased Pol ι expression in the breast tissue of women who carry BRCA2 mutations, suggesting that changes in stress responses may already be present in breast tissues without cancer.

"A person can inherit a BRCA2 mutation and carry it throughout life without necessarily developing cancer," Dr. Karaayvaz says. "We want to understand what happens in these cells during the years before cancer develops, and why some cells may eventually progress toward malignancy while others do not."

By investigating these early biological changes, Dr. Karaayvaz hopes her laboratory's research will eventually contribute to more individualized approaches to cancer risk assessment and prevention for people with inherited BRCA2 mutations.

What is a BRCA mutation?

• A BRCA mutation is a genetic abnormality in either the BRCA1 or BRCA2 gene that alters the gene's function. The mutation can be inherited or occur randomly.
• Some people inherit a harmful mutation in their BRCA1/2 gene, increasing their lifetime risk of developing breast cancer and other cancers.
• Both women and men can inherit BRCA mutations. However, not everyone who carries a harmful BRCA mutation will develop cancer.

How do BRCA mutations increase cancer risk?

BRCA1 and BRCA2 proteins act like a spellchecker for our DNA, helping cells repair damage and maintain the integrity of their genetic information. Faulty BRCA proteins can't repair DNA damage, which results in a problem called "replication stress."

Replication stress leads to typos – new gene mutations – when our cells divide and try to copy the DNA. Over time, additional changes in DNA can accumulate, potentially allowing some cells to grow uncontrollably and eventually form tumors.

How breast cells adapt to replication stress

The study builds on a longstanding collaboration between Dr. Karaayvaz's laboratory and breast cancer surgeon Zahraa Alhilli, MD. The team's latest paper, led by first author Kavya Vipparthi, PhD, focuses on Pol ι, a specialized protein that helps cells tolerate difficulties they encounter while copying their DNA.

Dr. Vipparthi and her team found increased Pol ι expression in the breast cells of women with BRCA2 mutations. Using experimental models, they also demonstrated that Pol ι helps BRCA2-deficient mammary epithelial cells adapt to the replication stress.

These findings suggest that breast cells may change how they respond to replication stress before cancer develops, offering new insights into the earliest biological processes associated with inherited breast cancer risk.

"We want to understand what happens in breast cells long before cancer develops," Dr. Karaayvaz says. "By studying how these cells respond and adapt to replication stress, we hope to uncover early biological changes that may eventually help us better understand cancer initiation and improve approaches to prevention."