Harvard Team Discovers Molecular Mechanism Underlying Many Breast Cancers

Through a combination of genomic and epigenomic analyses, along with experimental validation, a team led by Harvard Medical School researchers has uncovered a molecular mechanism that may be involved in many breast cancers. The finding, which is reported in this week's Nature, also directly implicates estrogen in the process. Focal copy-number amplification of oncogenes is known to play a crucial part in breast cancer, but how the cell of origin acquires amplicons and whether the process is associated with risk factors for the disease is unclear. To investigate, the researchers analyzed whole-genome sequencing, RNA sequencing, and epigenomic data on 780 breast cancer genomes, observing that focal amplifications are frequently connected to each other by inter-chromosomal translocations at their boundaries. Through further analysis, the researchers discover a process through which the oncogene neighborhood is translocated during the G1 phase to create a dicentric chromosome. The dicentric chromosome is then replicated and, as dicentric sister chromosomes, segregates during mitosis when a chromosome bridge is formed and then broken. The fragments are often circularized in extrachromosomal DNAs, explaining the amplification of oncogenes. Estrogen has a well-established role in promoting the growth of certain breast cancers, and the researchers noted that recurrent amplification boundaries and rearrangement hotspots were close to estrogen-binding areas on DNA. Experiments following up on this observation revealed that estrogen treatment induces DNA double-strand breaks in the in the estrogen receptor target regions that are repaired by translocations, pointing to a role for the hormone in generating initial translocations. "Our findings extend a growing body of work implicating estrogen-induced DNA breaks as an important driver of breast oncogenesis," the study's authors write.