In a recent study published in Nature, Peter Park, PhD, professor of biomedical informatics at Blavatnik Institute at Harvard Medical School (HMS) and senior investigator, and colleagues have identified “the original molecular trigger that initiates a cascade culminating in breast tumor development in a subset of breast cancers that are driven by estrogen.” Per the team, as many as one-third (31 percent) of breast cancer cases may arise through the newly identified mechanism.
When Park’s team, including Jake Lee, MD, PhD, a former research fellow in the Park lab and the study’s first author, analyzed the genomes of 780 breast cancer samples obtained from patients diagnosed with the disease, they didn’t find the classic oncogene-activating molecular patterns in any of the samples.
What is causing these tumors?
One of the mechanisms that activate oncogenes in humans is errors during cell division when normal or damaged chromosomes either get translocated and/or mispaired and overamplified. In this study, Lee and Park found “dicentric” chromosomes in 244 out of the 780 tumor samples. Meaning, the translocated chromosomes had formed bridges, but in this case, the bridge contained two different chromosomes.
Upon further analysis, they found that the chromosomes fused at “hot spots” near oncogenes, HER2 or ERBB2 and CCND1, and that these “hot spots” lay dangerously close to estrogen-binding areas. To explore estrogen’s role in genomic reshuffling and cancer gene activation, Lee and Park exposed breast cancer cells to estrogen and induced CRISPR-Cas9 breaks in the samples’ DNA.
Estrogen’s myriad role in breast cancer
The researchers found that when the cells mended their broken DNA, they initiated a repair chain that resulted in the same chromosomal rearrangement pattern Lee and Park had discovered. This establishes estrogen as a catalyst and cause of breast cancer and estrogen-induced DNA breaks as drivers of oncogenesis.
In a recent press release, Lee said that estrogen-suppressing drugs such as tamoxifen “may also prevent estrogen from initiating cancer-causing genomic rearrangements in the cells, in addition to suppressing mammary cell proliferation.”
The team believes that though the study may not have immediate therapeutic implications, it could help monitor patients’ response to treatments and aid clinicians detect tumor relapse in patients with a history of certain breast cancers.