Scientists at the Garvan Institute of Medical Research have discovered that some breast cancer cells survive treatment by slowing their growth to near-imperceptible rates, quietly spreading to distant organs before triggering relapse years later. A newly identified cellular pathway could become a target for prevention.
Breast cancer survivors are often told that reaching the five-year mark after treatment is a milestone. But for hundreds of thousands of women with the most common form of the disease, the threat of relapse does not end there. Now, researchers at the Garvan Institute of Medical Research in Sydney have uncovered a biological mechanism that helps explain why — and identified a molecular target that could eventually be blocked to prevent it.
The study, published May 11 in Nature Communications, focuses on estrogen receptor-positive (ER+) breast cancer, which accounts for the majority of breast cancer diagnoses. Even after five to 10 years of hormone therapy, up to 30% of patients develop what is known as late relapse — a recurrence that is often incurable and contributes heavily to the more than 3,300 breast cancer deaths recorded in Australia each year.
A Parallel Pathway to Relapse
Until now, scientists understood one key mechanism behind late relapse: cancer cells entering a state of complete dormancy in the bone or other organs, then “waking up” to cause metastasis years later. The new research documents an alternate route. Some cancer cells never truly go dormant — instead, they slow their division rate so dramatically that they effectively become invisible to standard hormone therapies, which are designed to target actively dividing cells.
“We have become very good at treating primary breast cancer, but late relapses remain a major challenge,” senior author Liz Caldon, an associate professor and lab head at the Garvan Institute who holds a conjoint appointment at St. Vincent’s Clinical School, Faculty of Medicine and Health, UNSW Sydney, said in a news release. “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.”
These slow-growing survivors are not merely a residual curiosity. Once these microscopic secondary tumors — called micrometastases — grow large enough to be detected or begin disrupting a vital organ such as the brain, liver, or bone, they can rapidly become life-threatening and are frequently resistant to chemotherapy.
Years of Lab Work, One Critical Discovery
Isolating these cells was itself a years-long challenge. Because the cells divide so infrequently, standard laboratory methods designed to capture proliferating cancer cells tended to bypass them entirely. The research team had to develop specialized techniques to cultivate them.
“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,” added first author Kristine Fernandez, a senior research assistant in the Caldon Lab. “These cells were migrating to organs like the bone and lungs, proving that speed isn’t everything when it comes to metastasis.”
When the team introduced these slow-growing cells into preclinical models, they found that the sluggish pace of division did nothing to limit the cells’ ability to travel through the body and colonize distant organs. In other words, slow growth is not the same as being harmless.
Zeroing In on the Rac1 Pathway
To understand what keeps these cells alive and mobile, the researchers looked at the molecular machinery driving their behavior. Using advanced biosensor imaging that allowed them to watch biochemical signals activate in real time inside living cells, they identified a cellular communication channel called the Rac1 pathway as a critical enabler. Rac1 governs cell movement, structural integrity and survival — functions that collectively allow slow-dividing cancer cells to persist through therapy and eventually spread.
Crucially, the team did not stop at identification. Using experimental Rac1 inhibitors, they were able to reduce both the size and the number of tumors in patient-derived laboratory models of breast cancer — a proof-of-concept result suggesting the pathway could be therapeutically targetable.
“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,” Caldon added.
Why It Matters for Patients — and Future Research
For the roughly 70% of breast cancer patients diagnosed with ER+ disease, treatment typically involves years of hormone therapy — a demanding regimen with significant side effects. One of the most difficult aspects of that journey is the uncertainty: patients and clinicians currently have limited tools to gauge whether long-term therapy is actually suppressing the slow-growing cells that could cause relapse a decade later.
The Caldon Lab is now launching follow-up investigations into whether Rac1 inhibitors could be deployed preventatively, before a relapse ever occurs.
“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,” added Caldon.
For young women diagnosed with breast cancer — a population that faces the full weight of a late-relapse risk stretching into their 30s, 40s and beyond — that kind of monitoring tool would represent a meaningful shift in how survival is defined and managed.