Australian researchers uncover molecular switch driving triple-negative breast cancer metastasis, pointing to CDK4/6 inhibitor repurposing
核心洞察
Australian researchers identified low miR-342 (搜索) levels and high E2F (搜索) pathway activity as drivers of metastasis in triple-negative breast cancer (搜索) (TNBC), published in EMBO Molecular Medicine.
In pre-clinical models, restoring miR-342 (搜索) markedly reduced cancer spread to organs including the lungs and bones.
The existing CDK4/6 inhibitor palbociclib significantly reduced metastatic tumor growth in models with low miR-342 (搜索), suggesting a repurposing opportunity.
Australian researchers have uncovered a molecular switch that drives the spread of triple-negative breast cancer (搜索) (TNBC), raising hopes for more effective treatments to stop one of the most aggressive forms of breast cancer from metastasizing. The study, undertaken by Adelaide University (搜索) and the Olivia Newton-John Cancer Research Institute and published in EMBO Molecular Medicine, found that patients with low levels of a naturally occurring molecule known as miR-342 (搜索) and high activity of a cancer-driving pathway called E2F (搜索) were more likely to develop metastatic disease.
TNBC is the subtype responsible for some of the poorest outcomes because it lacks the hormone receptors that make many other breast cancers treatable with existing therapies that target these receptors. Triple-negative breast cancer (搜索) accounts for around 10–15% of Australia's approximately 21,000 breast cancer diagnoses each year but causes a disproportionate number of breast cancer deaths because of its aggressive nature and tendency to spread rapidly to distant organs.
A master regulator of cancer progression
Co-senior author Associate Professor Philip Gregory, from Adelaide University (搜索)'s Centre for Cancer Biology and SA Pathology, said metastasis remains the greatest challenge in treating triple-negative breast cancer (搜索). "Most deaths from breast cancer occur because the cancer spreads to other parts of the body, rather than being caused by the primary tumor itself," he said.
The team discovered that miR-342 (搜索) acts as a master regulator of an entire network of genes involved in cancer progression. "When miR-342 levels fall, the E2F (搜索) pathway becomes overactive, allowing dormant cancer cells that have already travelled through the body to grow into dangerous secondary tumors," Associate Professor Gregory explained.
In pre-clinical models, the team demonstrated that restoring miR-342 (搜索) levels markedly reduced the spread of breast cancer to other organs, including the lungs and bones.
Repurposing an existing therapy
The researchers also showed that the existing breast cancer drug palbociclib — a CDK4/6 inhibitor currently used to treat advanced hormone receptor-positive breast cancer — significantly reduced the growth of metastatic tumors in models with low miR-342 (搜索).
"The exciting aspect of this discovery is that drugs targeting this pathway already exist. CDK4/6 inhibitors are routinely used for patients with advanced hormone receptor-positive breast cancer, and our findings suggest they could also benefit a carefully selected group of patients with triple-negative disease," Associate Professor Gregory said.
The researchers found that administering palbociclib after cancer cells had already spread was particularly effective in preventing microscopic metastatic tumors from growing. "Rather than shrinking the primary tumor, this treatment may prove most valuable by stopping tiny metastatic deposits from developing into life-threatening secondary cancers," the authors noted.
Toward a personalized treatment approach
Co-senior author Professor Robin Anderson, from the Olivia Newton-John Cancer Research Institute, said understanding why cancers spread beyond the primary tumor is essential because metastatic disease is responsible for most breast cancer deaths. "Primary tumors can often be treated successfully with surgery or local therapies, but once cancer spreads throughout the body it becomes far more difficult to control," Professor Anderson said.
"Triple-negative breast cancer (搜索) is incredibly diverse, and that's one of the reasons it has been so challenging to develop targeted treatments," she added. "Our study identifies a distinct subgroup of patients whose cancers share a common biological weakness, opening the door to a much more personalized treatment approach."
The findings suggest that measuring miR-342 (搜索) levels could help identify a subset of women with triple-negative breast cancer (搜索) who are most likely to benefit from treatment with CDK4/6 inhibitors, potentially allowing an existing therapy to be repurposed for one of the deadliest forms of breast cancer. The researchers say the next step is to validate the findings using patient-derived pre-clinical models before progressing to clinical trials.