Scientists find genetic switch that may fuel breast cancer’s spread

Cancer researcher Robert Weinberg at his office at the Whitehead Institute for Biomedical Research
Cancer researcher Robert Weinberg at his office at the Whitehead Institute for Biomedical Research –Suzanne Kreiter/File photo/2004

As tools for detecting cancer early have improved, medical understanding simply hasn’t kept up. Finding tumors early is of limited help when doctors still struggle to tell which breast cancers are highly aggressive and likely to spread and which are slow-growing and benign, leading to repeated debate over the benefits and possible harm of screening.

A new study may offer a valuable clue about how cancers become aggressive, identifying a genetic switch that in some breast cancer cells is poised to be flipped on by signals from the surrounding tumor environment. When the switch is triggered, it helps transform non-aggressive cells into cancer stem cells capable of proliferating and spreading. The switch, researchers found, is positioned differently in two types of breast cancer — one that has a greater survival rate, and one that is more prone to spread.


“The fact of the matter is when it becomes a cancer stem cell, it acquires tumor-initiating ability, capable of spawning an entire new tumor,’’ said Robert Weinberg, a founding member of the Whitehead Institute for Biomedical Research in Cambridge who led the research. “It could be that we’ve stumbled on what may be the root cause between the two different kinds of cancer.’’

Weinberg cautioned that the work, published this month in the journal Cell, was basic science and it is far too soon to know its relevance to understanding human disease. But it may help explain how cancers in the same organ can take such different paths.

Weinberg and colleagues discovered that whether tumor cells responded to signals sent by the surrounding microenvironment depended on the status of a gene called ZEB1. A subtype of breast cancer called luminal cancers, which generally have a far better prognosis, have the ZEB1 gene “locked down,’’ Weinberg said. That means even when those cancers are exposed to environmental triggers, ZEB1 doesn’t get activated.

In basal cancers, which tend to be aggressive — with about a quarter of patients dying within five years of their diagnosis — that gene is primed and ready to spring into action with the right triggers.


“This may be getting us very close to the root cause of the profound difference between the two different kinds of cancer,’’ Weinberg said. “At the same time, it may one day yield some kind of diagnostic where one could look at the configuration of the ZEB1 gene and discern whether it’s locked down or in the poised configuration.’’

Weinberg said he hoped to examine human breast cancer tissue samples next, to see if the status of the gene was predictive of how aggressive patients’ cancers were. The process may not be straightforward; there are many signals sent by the tumor microenvironment. But it is possible, Weinberg said, that the same activating mechanism might account for the difference in virulence of other cancers in which oncologists struggle to distinguish those that are benign from those that will spread throughout the body.

If the gene’s readiness to be triggered does turn out to be an important factor in turning cancers aggressive, it could be a powerful way to predict the course of disease and target treatment.

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