While breast cancer treatments continue to improve, the disease can sometimes resurface decades after remission. This relapse risk stems from cancer cells that break away from the original tumor and remain dormant in the breast or other organs. Scientists know little about what triggers cancer cells to fall asleep — and even less about what causes them to awaken.
A new study led by Prof. Yosef Yarden's lab at the Weizmann Institute of Science, published Tuesday in Science Signaling, reveals a mechanism that puts breast cancer cells into dormancy and explains why they often return more aggressive than before.
Breast cell metamorphosis
From embryonic development through puberty, pregnancy and breastfeeding, breast tissue undergoes significant changes. These shifts are possible because breast cells transition from an early, mesenchymal state — in which they are round, fast-dividingand highly mobile — to a mature, epithelial state, where they are cuboidal, slow-dividing and stationary.
Normally, this transition is tightly controlled. But when it goes awry, cells can begin dividing rapidly and become malignant. Cancer typically starts when mature cells revert to their earlier, fast-dividing form, allowing them to build tumors and spread. Later, however, cancer may exploit the reverse process: dispersed cells can mature again, becoming stationary — in other words, dormant.
Given the similarities between normal epithelial cell maturation and cancer cell dormancy, researchers hypothesized they could deliberately induce dormancy in breast cancer cells by mimicking this natural process.
Using a three-dimensional tumor model developed by Dr. Dalit Barkan at the University of Haifa, researchers in Prof. Yarden’s lab, led by Dr. Diana Drago-Garcia, engineered aggressive triple-negative breast cancer (TNBC) cells to produce high levels of OVOL proteins, which are key players in natural epithelial maturation.
Can dormancy be prevented altogether?
“Our efforts focus on preventing the awakening of cancer cells," explained Prof. Yarden. "In their dormant state, they’re not dangerous. If we don't allow them to go dormant, they continue threatening the patient’s life."
Using their engineered model, the researchers demonstrated that overexpression of OVOL proteins halts the cell cycle of aggressive cancer cells and sends them into dormancy. In parallel, experiments in mice implanted with human breast tissue showed that OVOL overexpression slowed tumor growth.
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OVOL proteins transfer breast cancer cells from an active state (right) to a dormant state (left)
(Photo: Weizmann Institute of Science)
At first glance, these findings seem promising for cancer treatment. However, researchers noted that breast cancer patients’ tissues often show high levels of one OVOL protein, OVOL1.
They hypothesized that while OVOL1 initially suppresses cancer growth, it helps tumors survive long-term by enabling cells to hide undetected. Once bodily conditions change and OVOL1 levels drop, the cancer reawakens — more aggressive and dangerous than before.
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Given OVOL1's double-edged role, could it be controlled therapeutically?
“It would be extremely difficult to inhibit this protein," said Prof. Yarden. "OVOL1 isn't an enzyme or a receptor and we prefer targeting proteins that regulate its activity."
Estrogen’s surprising role
Armed with these findings, researchers investigated how tumors might manipulate OVOL levels to toggle cancer cells between dormancy and activity. They found that growth factors increase OVOL1 expression, while estrogen reduces it.
Accordingly, they showed that breast cancer patients whose tumors had low estrogen receptor levels and high OVOL1 levels faced a higher risk of developing aggressive disease with poorer survival rates.
“These findings could pave the way for strategies to prevent cancer cells from either entering or exiting dormancy,” said Prof. Yarden. “For example, after menopause, fat tissue becomes the main producer of estrogen.
"Weight gain later in life among women who had breast cancer at a young age could boost estrogen levels, reduce OVOL1 expression and raise the risk of dormant cancer cells waking up.” Future studies in animals and humans will test this hypothesis.
Dangerous changes during 'dormancy'
One major mystery remains: Why do breast cancers often return more aggressive after dormancy?
To answer this, the team traced the molecular chain through which OVOL1 induces dormancy. They discovered that this pathway leads to an accumulation of unstable molecules known as free radicals.
These free radicals damage various cell components, halt cell division and push cells into dormancy — a surprising link never before associated with cancer cell sleep.
Working with Prof. Shiloh at Tel Aviv University, the researchers further showed that prolonged stress from free radical buildup alters the expression and function of key proteins in the cell nucleus, where DNA resides.
As a result, the genetic material becomes oxidized and damaged, impairing the function of three critical DNA repair proteins. The scientists believe this accumulation of DNA damage — coupled with faulty repair mechanisms — explains why cancers that awaken are often riddled with mutations, highly aggressive and harder to treat.
How much do aging, hormonal changes and rising free radical levels contribute to the risk of dormant cancer reawakening?
“All of these are prime suspects,” said Prof. Yarden. “They’re closely tied to aging, hormonal shifts, body composition changes and lifestyle factors, including diet.”
“Contrary to the common belief that dormant cancer cells are simply frozen in time, we showed that they undergo profound genetic changes during their ‘dormancy,’” he added. “This aligns with findings from autopsies of aggressive breast tumors."
Prof. Yarden noted that breast cancer isn't the only type that can go dormant. Understanding these mechanisms could help develop treatments for many cancers.
Could this mechanism explain recurrence in other cancers like melanoma or lung cancer?
“We strongly suspect it’s a general mechanism shared across several cancer types,” said Prof. Yarden. "Future research will explore these questions."