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Madalena Tarsounas

BACKGROUND

BRCA1 and BRCA2 genes are mutated in about a quarter of familial breast and ovarian cancers. However, familial cancers represent only a small fraction of all cancers (Figure 1). In recent years, whole genome sequencing of large number of human tumours revealed that a significant fraction of non-familial breast and ovarian cancers carry BRCA1and BRCA2 mutations and that these mutations are also found in other types of sporadic cancer (Figure 2). Importantly, triple negative breast cancers, associated with one of the most aggressive forms of the disease, are significantly enriched in BRCA1 and BRCA2 mutations.

                             Figure 1 - graph showing breakdown of breast and ovarian cancers.jpg

   Figure 1

Figure 2 - BRCA1 and BRCA2 mutations in sporadic cancer types.jpg

     Figure 2


A conundrum regarding the breast cancer-promoting BRCA1 and BRCA2 gene mutations is that their introduction into normal cells causes cell cycle arrest and embryonic lethality, and not the rampant cell proliferation characteristic of tumours bearing the same mutations. One entry point into understanding this paradox is the key role of BRCA1 and BRCA2 proteins in facilitating accurate DNA replication by helping stalled forks to re-start (Figure 3). Consequently, cells with compromised BRCA1/2 function accumulate stalled replication forks, which, in turn, leads to replication-associated DNA damage. These pathological DNA lesions are lethal to normal cells, where DNA damage checkpoints and responses are functional. However, cancer cells lack DNA damage responses; they can proliferate and become tumourigenic in spite of DNA damage accumulation.

 

Figure 3 - BRCA1 and BRCA2 proteins facilitate accurate DNA replication.jpg

Figure 3

Work conducted in my laboratory aims to unravel the mechanisms underlying replication failure in BRCA1/2-deficient cells and how this knowledge can be exploited for the development of novel treatments that could selectively kill tumour cells with compromised BRCA1/2 function.

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