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2024-03-29| R&D

Innovative Cellular Mapping of BRCA-Related Breast Cancer Findings Reveals Novel Therapeutic Targets

by Bernice Lottering
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Immune cell exhaustion observed in breast tissue from carriers of BRCA1 and BRCA2 mutations long before breast cancer develops. Credit: Sara Pensa, University of Cambridge’s Department of Pharmacology.

Researchers at the University of Cambridge have identified novel mechanisms underlying the pathogenesis of breast cancer. Data derived from the world’s largest human breast cell catalog has indicated that early cell changes in carriers of BRCA1 and BRCA2 gene mutations increase the risk of breast and ovarian cancer development. These findings introduce new targets for therapeutic intervention and highlight the potential of existing immunotherapies in BRCA mutation carriers. Moreover, the creation of the most extensive collection of human breast cells stemming from this research provides an available foundation for future investigations.

Understanding Early Cell Changes in BRCA Gene Mutation Carriers

Researchers at the University of Cambridge have unveiled crucial insights into breast cancer development. Their findings, published in Nature Genetics and titled “A single-cell atlas enables mapping of homeostatic cellular shifts in the adult human breast”, describe how early cell changes in BRCA1 and BRCA2 genetic mutations are associated with a heightened risk of ovarian and breast cancer in healthy individuals. The study identified that in carriers of these mutations, certain changes occur in the immune cells of breast tissue well before the cancer manifestation. 

While everyone possesses BRCA1 and BRCA2 genes, it is the mutations in these genes (which can be inherited) that directly influence risk of breast cancer development. In this work, these mutated genes show signs of malfunction, also known as “exhaustion”. Essentially, the immune cells are incapable of removing compromised or damaged breast cells. It is these residual cells that eventually develop into cancer. For the first time, the presence of these “exhausted” immune cells, usually only observed in late-stage tumors, has been extensively documented in non-cancerous breast tissue.

“Our findings indicate that in individuals with BRCA mutations, the immune system is unable to eradicate impaired breast cells—consequently, these cells appear to inhibit the activity of immune cells,” stated Walid Khaled, PhD, a professor at the University of Cambridge’s department of pharmacology and Wellcome-MRC Cambridge Stem Cell Institute, and senior author of the study.

A Novel Avenue of Therapeutic Research 

These findings highlight the importance of identifying early cellular changes to devise preventative strategies beyond surgical intervention. The use of immunotherapies as preventative measures in carriers of BRCA breast cancer gene mutations is not widely explored. This approach would offer an alternative to the conventional risk-reducing mastectomies in patients at increased risk. 

Currently several medications are offered that can circumvent the inhibition of immune cell function, although their approval is largely limited to late-stage disease. However, the unpredictable nature of late-stage disease often poses significant challenges to management strategies. Furthermore, despite the numerous advances in drug development, tumors demonstrate resilience and often evade treatment efficacy. Therefore, the concept of using these current medications in a preventative fashion holds enormous potential and has not been largely explored until now.

Cancer Research UK has awarded the researchers a “Biology to Prevention Award” to conduct trials on this preventative strategy in mice. Success in these trials could lead to the initiation of a pilot clinical trial involving women with BRCA gene mutations. “The best way to prevent breast cancer is to really understand how it develops in the first place. Then we can identify these early changes and intervene,” said Khaled.

The Largest Breast Cell Atlas: A Wealth of Information

By incorporating and analyzing healthy breast tissue samples from 55 women across a range of ages, 800,000 cells were documented, encompassing all different types of breast cells. This Human Breast Cell Atlas serves as a comprehensive resource for researchers worldwide, offering invaluable data on breast cell types, their alterations during pregnancy and aging, and their association with breast cancer risk factors such as Body Mass Index (BMI), menopausal status, contraceptive use, and alcohol consumption. This study aimed to investigate the interaction of these various risk factors by characterizing the diverse cell types in the human breast across different physiological states. Using single-cell RNA sequencing, the researchers identified the distinct breast cell types, their respective genetic identity and affiliated function as well as the active genes in individual cells.

Joint first co-authors of the study, Austin Reed and Dr. Sara Pensa, emphasized the significance of understanding the diverse breast cell types and their changes with pregnancy and age in influencing breast cancer risk. They underscored the importance of prevention as the most cost-effective approach to address global breast cancer disparities, benefiting both low-income and high-income countries by improving disease outcomes.

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