Cancer with a Twist: Protein instrumental in breast-cancer metastasis

A protein called Twist, which orchestrates gene activity in cells, facilitates the spread of some breast cancers, according to a study in the June 25 Cell.

Because it induces a cell to disengage from its surroundings and float freely, Twist lets nascent cells migrate. Without such movement, embryonic development would come to a halt. This central role in cell migration has also implicated the protein in cancer metastasis.

By screening dozens of mouse genes, physician Sridhar Ramaswamy of Harvard Medical School in Boston and his colleagues found that the one encoding Twist was active in breast cancer that had arisen spontaneously. Mice displaying forms of the cancer most prone to spread had the highest amounts of Twist in their tumors.

Twist binds to DNA, switching on some genes and turning off others. For example, one Twist-regulated gene encodes a protein called E-cadherin, which works like two-sided sticky tape to hold together cells. Ramaswamy’s team has now shown that Twist turns off the gene that encodes E-cadherin in breast-cancer cells. That drop in E-cadherin production may permit the malignant cells to slip their moorings and travel throughout the body.

To further clarify Twist’s role in metastasis, Ramaswamy and his coworkers injected highly metastatic breast-cancer cells into mice. Some of the cells were genetically altered to obstruct production of Twist, while others were unimpaired. Animals receiving the Twist-disabled cells had fewer cancer cells in their blood, indicating that the protein helps cells migrate.

Moreover, while traces of the cancer showed up in lung tissues of both sets of mice, it proliferated into lung tumors only in mice with Twist. This difference may reflect Twist’s role as a master regulator of genes beyond those participating in migration.

The researchers also studied human breast-cancer tissue. They found evidence that women whose cancer originated in the milk-producing lobes of the breast have concentrations of Twist more than 1.5 times as great as women with cancer originating in the mammary ducts. Lobular breast cancer is more likely than ductal cancer to metastasize.

Scientists don’t yet know why cancer cells—and particularly these aggressive lobular breast-cancer cells—produce excess Twist.

The new study was “very carefully done,” says Mary Jo Fackler, a molecular biologist at Johns Hopkins Medical Institutions in Baltimore. It solidifies Twist as a molecule worth studying to sort out the biological underpinnings of metastasis. Fackler’s group had already included Twist in their tests to identify factors that promote the spread of breast cancers through the body.

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