Study sheds light on origins of breast cancer in people with BRCA2 mutations

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A pioneering study led by Professor Ashok Venkitaraman of the National University of Singapore’s Cancer Science Institute (CSI Singapore) and Dr Mona Shehata of the University of Cambridge (UK) has uncovered important insights into the distinct impact of BRCA2 mutations on the breast. Tissue cells shed light on the early development of breast cancer in people with BRCA2 mutations. The research has been published in prestigious journals Nature communication on 25 August 2023.

Breast cancer is a serious concern for people with BRCA2 mutations, with about 70 percent of carriers developing the disease by age 80. Although the role of BRCA2 in DNA repair and as a tumor suppressor to protect cells from DNA replication stress is well documented, little is known about the developmental pathways of breast cancer in BRCA2 mutation carriers.

Despite the high risk faced by BRCA2 mutation carriers in developing breast cancer, there is a serious lack of understanding of how these mutations affect the different cell types of the mammary gland. The goal of our study is to uncover the earliest events that precede cancer formation within the breast tissue microenvironment so that early intervention strategies can be better designed.”

Professor Venkitaraman, corresponding author of the study and director of CSI Singapore

A detailed investigation using long-term mammary organoid cultures revealed that healthy mammary glands do not predispose to tumor formation. However, when exposed to stress during DNA replication, the population of hormone receptor-negative (HR-) luminal cells is significantly expanded. Importantly, proliferation was particularly robust in mammary gland organoids harboring BRCA2 mutations.

The study also discovered that HR-luminal cells with BRCA2 mutations exhibit enhanced organoid formation and survival under replication stress. Further analysis at the single-cell RNA-sequencing level identified elevated stemness markers and type I interferon responses in these cells, preferentially favoring the growth of HR-luminal cells. It also showed that HR-luminal BRCA2-mutant cells became more susceptible to tumor formation after multiple stressors, suggesting that distinct mechanisms drive the transformation of HR- and HR+ tumors, especially in BRCA2 mutation carriers.

It is important to understand the mechanisms that drive the development of early-stage cancers in order to classify breast cancers into their distinct subtypes (triple-negative breast cancers, and hormone-positive and HER2-positive breast cancers, among others), so that targeted, early treatments can be directed to achieve positive outcomes. . result

The team hopes to further validate their key observations from this study in mammary glands from preventive mastectomy cases among BRCA2 carriers. This will strengthen their evidence for designing early intervention strategies, which will provide guidance to clinicians caring for individuals with BRCA2 mutations.


Journal Reference:

Najafabadi, M.G., etc. (2023). The replication response to replication stress selectively expands a subset of Brca2-mutant mammary epithelial cells. Nature communication.

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