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Researchers at Garvan Institute of Medical Research have identified a previously underappreciated mechanism that may explain why some breast cancers return many years, even decades, after apparently successful treatment.

The study, published in Nature Communications, reveals that certain estrogen receptor-positive (ER+) breast cancer cells survive therapy not by entering complete dormancy, but by continuing to divide at an extraordinarily slow pace. These stealth-like cells can gradually form microscopic secondary tumors that remain undetectable for years before eventually triggering metastatic relapse.

The findings offer new insight into one of the most persistent challenges in breast cancer care: why relapse can occur long after patients are considered cancer-free.

The long shadow of ER-positive breast cancer

ER-positive breast cancer is the most common subtype of breast cancer and is typically treated with hormone therapies designed to block estrogen signaling. These treatments are often highly effective at eliminating actively dividing tumor cells.

However, ER-positive disease has a unique clinical problem: recurrence risk persists for decades.

Even after five to ten years of endocrine therapy, up to 30% of patients can eventually develop metastatic relapse. Once breast cancer spreads to distant organs such as bone, lung, or brain, the disease becomes largely incurable.

Traditionally, relapse has been attributed to dormant cancer cells—cells that enter a state of complete hibernation before later “waking up.” But the new study suggests this may not be the only pathway.

“We have become very good at treating primary breast cancer, but late relapses remain a major challenge,” said Liz Caldon, associate professor and senior author of the study.

Not dormant—just incredibly slow

The researchers discovered that some breast cancer cells never fully stop proliferating during therapy. Instead, they survive by drastically slowing their rate of division.

This subtle distinction may be clinically critical.

Rather than entering complete cellular arrest, these cells continue to grow at an almost imperceptible pace, allowing them to evade therapies that primarily target rapidly dividing cells.

“Instead, they survive by growing extremely slowly in the background, until a tiny speck becomes a pebble,” Caldon explained.

Over many years, these microscopic lesions, known as micrometastases, can gradually expand until they become clinically detectable or disrupt vital organs.

The work challenges a long-standing binary view of cancer persistence in which tumor cells are considered either actively proliferating or fully dormant. Instead, the findings support the existence of an intermediate “slow-cycling” state that may be particularly effective at evading treatment.

Isolating the slowest cancer cells

Studying these rare cells was technically difficult because of their exceptionally slow growth.

The research team spent years isolating and cultivating these populations in the laboratory. Once established, they introduced the cells into preclinical models to determine whether slow proliferation impaired metastatic potential.

It did not.

Despite dividing slowly, the cells retained the ability to migrate throughout the body and colonize distant organs such as bone and lung.

“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,” said Kristine Fernandez, 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.”

The findings reinforce a growing understanding in oncology that aggressive cancer behavior is not solely defined by rapid proliferation. Cellular adaptability and survival under therapeutic pressure may be equally important.

Rac1 emerges as a potential therapeutic target

After identifying the slow-growing cells, the researchers investigated what allowed them to survive.

The study pinpointed a signaling pathway centered on Rac1, a protein involved in cell movement, structural organization, and survival. Using advanced biosensor imaging, the team directly visualized Rac1 pathway activation inside live slow-growing cancer cells.

Inhibiting this pathway appeared therapeutically promising.

Experimental Rac1 inhibitors significantly reduced tumor size and tumor number in patient-derived breast cancer models.

This suggests that targeting Rac1-dependent survival programs could potentially eliminate slow-growing residual cancer cells before they evolve into clinically significant metastases.

Rethinking cancer relapse biology

The findings contribute to a broader shift in cancer biology away from viewing residual disease as uniformly dormant.

Instead, tumors may contain multiple survival states, including cells that persist through continuous but ultra-slow proliferation. These populations may be especially dangerous because they remain biologically active while escaping conventional therapeutic detection.

The work also raises important clinical questions about long-term endocrine therapy. Current treatment durations are largely standardized, yet some patients may harbor persistent slow-cycling tumor cells despite years of therapy.

“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,” Caldon said.

Toward preventing late relapse

The study’s implications extend beyond breast cancer alone. Slow-cycling drug-tolerant cancer cells have increasingly been identified across multiple tumor types, including melanoma, lung cancer, and leukemia.

By identifying a concrete signaling mechanism underlying this state in ER-positive breast cancer, the research provides a potential therapeutic entry point for preventing relapse before metastatic disease emerges.

The next challenge will be determining whether Rac1 inhibitors, or similar approaches targeting slow-cycling survival programs, can safely and effectively eliminate residual cancer cells in patients.

If successful, such strategies could fundamentally alter how clinicians approach long-term relapse prevention in breast cancer, shifting the focus from simply suppressing visible disease to actively eradicating the hidden cellular reservoirs that remain years after treatment ends.

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