A new study by the Garvan Institute of Medical Research has uncovered a hidden mechanism explaining why breast cancer can return many years after successful treatment. Published in Nature Communications , the research revealed rogue cells that change their programming to allow them to divide at a remarkably slow pace, meaning they could form microscopic tumours that silently tick away in distant organs, evading detection for decades.
This research addresses a major challenge for patients with estrogen receptor-positive (ER+) breast cancer, where the possibility of relapse can linger for years after being declared cancer-free. Even after five to 10 years of initial hormone therapy, up to 30% of patients develop incurable relapse, heavily contributing to the more than 3,300 women who die from breast cancer in Australia every year.
Relapse is known to be caused by cancer cells lying dormant in the bone or other organs before 'waking up' to cause metastasis. The new research provides evidence on a parallel pathway by which stealthy cancer cells develop into secondary tumours – findings which could uncover new approaches to prevent metastasis.
"We have become very good at treating primary breast cancer, but late relapses remain a major challenge," says Associate Professor Liz Caldon, Lab Head at the Garvan Institute and senior author of the study. "While we know some cancer cells can go into a state of complete hibernation, we characterised an important alternative pathway that enables cells to never truly stop dividing during treatment. Instead, they survive by growing extremely slowly in the background, until a tiny speck becomes a pebble."
Even though these cancer cells are slow-growing, they are far from harmless. Once these 'micrometastases' – tiny secondary tumours – cross the threshold of detection or disrupt a vital organ like the brain or bone, they can become a life-threatening relapse that is notoriously resistant to chemotherapy.
"For a long time, the idea that extremely slow-growing cells could drive relapse was just a theory. We've found evidence for the way this could happen in ER-positive breast cancer. By identifying the pathways that are important in these slow-growing cells we have a new lever to potentially prevent these deadly outcomes," Associate Professor Caldon says.
Escaping therapy by slowing down
While standard hormone treatments are highly effective at clearing out the vast majority of active breast cancer cells, a tumour is not uniform. The researchers found that some cancer cells naturally divide at a very slow rate when treated with therapy, and the slow rate inadvertently protects them from treatment. As the treatment successfully neutralises the fast-growing cancer cells, these slow-growing survivors are left behind to cause cancer relapse down the track.
To understand this process, the team spent years isolating and cultivating exceptionally slow-growing breast cancer cells in the laboratory. When they introduced these cells into preclinical models, they discovered that a slow growth rate did not limit the cancer's ability to spread throughout the body.
"It took years to isolate these specific cells because they were dividing so slowly, almost in defiance of how we typically expect cancer to behave. But once we observed them in action, we realised that a slow clock doesn't mean a stopped clock," says Kristine Fernandez, Senior Research Assistant in the Caldon Lab and first author of the study. "These cells were migrating to organs like the bone and lungs, proving that speed isn't everything when it comes to metastasis."
A new target for treatment
The researchers then pinpointed what drives these slow-growing cells – a cellular communication channel known as the Rac1 pathway. Rac1 is critical for cell movement, structure and survival. By using advanced biosensor imaging, the team visualised the Rac1 pathway activating inside live, slow-growing cancer cells.
Importantly, the researchers demonstrated that blocking this pathway could effectively shrink the cancer. Using experimental Rac1 inhibitors, the team successfully reduced the overall size and number of tumours present in patient-derived lab models of breast cancer.
Looking ahead, the Caldon Lab is launching new investigations to determine if Rac1 inhibitors could be used preventatively to stop the cancer coming back.
"If we can understand the specific biology of these slow-growing cells, we might eventually be able to offer better ways to track whether a decade of hormone therapy is actually working and ultimately prevent recurrence for patients living with the threat of relapse," says Associate Professor Caldon.
