Scientists in Toronto have uncovered 81 previously unknown genes that drive basal-like breast cancer (BLBC), one of the most aggressive and difficult-to-treat forms of the disease, using a novel gene-editing tool that works directly inside living tumors.
The research, published in Nature, provides the most detailed view yet of how the chromosomal chaos characteristic of BLBC — where entire stretches of chromosomes are lost or copied repeatedly — actually fuels cancer growth.
BLBC, also called triple-negative breast cancer, disproportionately affects younger women of color. Its tumors lack the three receptors that clinicians commonly use to target other breast cancers, leaving patients with fewer precision therapy options. While five-year survival rates for many breast cancers approach 95 percent, BLBC remains far deadlier.
"In many types of breast cancer that have been extensively researched, the five-year survival rate is around 95 percent," said Dr. Daniel Schramek, the study's senior author and Deputy Director of Discovery Research at Sinai Health in Toronto. "In this one subset, we don't know what the driver of the cancer is and therefore, it has some of the worst outcomes for patients."
The team developed a new tool called CRISPR-KOALA (Knockout and Activation Linked Assay) that can both silence genes and switch them on within the same living animal. This allowed researchers to mimic both the deletion and duplication of genes caused by aneuploidy — the abnormal chromosome numbers seen in BLBC.
Using CRISPR-KOALA to screen more than 3,700 genes located on commonly altered chromosomes, the researchers identified 81 genes that had never before been recognized as cancer drivers. Crucially, 90 percent of these newly identified genes were not detected in standard cell culture experiments, highlighting why studying cancer in living tumors matters.
One gene, PLGRKT, emerged as an especially powerful driver. It helps cancer cells survive in oxygen-deprived regions deep inside tumors by enabling them to switch to alternative metabolic processes — essentially allowing them to keep generating energy when oxygen is scarce.
The discovery opens potential new avenues for targeted treatments against a cancer that has long resisted them.
