Discovery by uOttawa researcher could reduce the need for preventive mastectomy in BRCA1-mutated breast cancer

Posted on Tuesday, June 14, 2016

One in nine Canadian women is expected to develop breast cancer throughout her lifetime, and one in 30 will die from it. Preventing breast cancer at the cellular level however, may be a possibility, after research by Dr. Christine Pratt at the University of Ottawa uncovered why breast cells with the BRCA1 gene mutation are at high risk for evolving into tumours.

BRCA1 is a tumour-suppressor gene that repairs DNA. It protects cells from potentially harmful mutations as the cells copy their DNA in order to divide. When a woman inherits a mutation of the BRCA1 gene, the gene may not be able to repair faulty DNA, increasing the risk of genetic mutations and cancer.

A woman’s lifetime risk of developing breast cancer can increase to 80% if she has inherited a harmful BRCA1 mutation, pushing many women to opt for a prophylactic mastectomy as a prevention method. Awareness of BRCA1 has increased in recent years after actress Angelina Jolie went public with her decision to undergo a double preventive mastectomy following confirmation that she was a carrier of the gene.

During a monthly cycle in humans, stem cells within the breast undergo a phase called proliferation, where cells rapidly multiply in response to the hormone progesterone. Dr. Pratt and her team have discovered that if these cells lack BRCA1, they accumulate DNA damage as they multiply, which triggers NF-κB, a protein complex normally involved in the proliferation of immune cells. “The activation of NF-κB leads to increased cell proliferation that no longer requires progesterone, resulting in even more DNA damage,” says Pratt, Associate Professor of Cellular and Molecular Medicine at the Faculty of Medicine. “In cells with a BRCA1 mutation, the DNA cannot be properly repaired.”

Together, these factors strongly increase the risk of more mutations that can lead to breast cancer. The finding that NF-κB is pivotal to the development of breast cancer in BRCA1 mutation carriers opens the door for prevention therapies targeting the NF-κB protein.

“Importantly, we have also found that a substance called dimethylaminoparthenolide (DMAPT), which is a synthetically modified version of the natural compound, parthenolide, which, when given to BRCA1-deficient mice, eliminates these abnormal stem cells for extended periods. Our results suggest that this treatment could be used to forestall or reduce the need for prophylactic mastectomy,” adds Pratt.

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