Twist Protein Significant Contributor to Breast Cancer Metastasis, Study Finds
Breast cancer tumor cells' ability to travel through the body and form distant tumors appears to rely on their ability to appropriate a "sleeper protein" that plays an important role in early embryonic development, according to a study published in the June 25 Cell.
The protein, known as Twist, regulates genes and is critical to cellular communication and cell allocation into various tissues during embryonic development. Twist typically remains dormant after embryo development is complete. However, in a study by a research team from the Whitehead Institute, led by Dr. Robert Weinberg, breast cancer tumor cells were shown to reactivate the protein. Thanks to this molecular hijacking, "cancer cells acquire in one fell swoop many of the abilities they need to execute the complex stages of metastasis," said Dr. Weinberg.
The study, funded in part by the National Cancer Institute (NCI), involved both a mouse model and tissue samples of human breast cancers, with each step in the investigation implicating Twist as a critical component of metastasis. The gene that encodes for Twist, the team found, was highly expressed in metastatic mouse tumor cell lines but not in nonmetastatic lines. To prove this point, metastatic mouse tumor cells devoid of Twist were injected into the mammary pads of mice. The result: Primary tumors formed but were unable to metastasize.
In addition, cultures of blood samples from mice showed that Twist aids tumor cells' efforts to slip into the blood stream; other components of the study may show how. In tests on normal mammalian cells, the introduction of cells that express Twist promoted an epithelial-mesenchymal transition (EMT), a molecular event that results in a cellular conversion, causing bound epithelial cells to lose the protein E-cadherin, separate from each other, alter their shape, and acquire the proteins needed for motility and invasion.
Finally, based on the results of the earlier tests, team members from Brigham and Women's Hospital reanalyzed data on 57 tumor samples from 3 aggressive human breast cancer subtypes. Of the 3, Twist was expressed in 70 percent of invasive lobular carcinomas - a subtype characterized by almost complete E-cadherin depletion.
"We were seeing the same phenotype and gene expression correlation in human breast tumors," said paper co-author Dr. Andrea Richardson, a pathologist at Brigham and Women's Hospital.
A number of previous studies have shown that loss of E-cadherin expression occurs in many carcinomas "which was correlated with a more invasive and metastatic phenotype," said study lead author Dr. Jing Yang. "Therefore, we think that suppression of E-cadherin by Twist could be an important function" in cancer metastasis.
Dr. Suresh Mohla, chief of the Tumor Biology and Metastasis Branch in NCI's Division of Cancer Biology, concurs. "Together, the findings present a good picture that the activation of Twist and Twist-induced EMT are important components for tumor metastasis," he said.
"There are many barriers in metastasis, and it is considered a very inefficient process," Dr. Mohla continued. "A normal tumor may shed millions of cells a day, but very few survive. These investigators showed that tumor cells are very clever and are able to overcome these barriers by appropriating a very latent protein that helps them move in and out of blood and into tissues, form new colonies, and grow.
"Other studies have pointed to genes that are important components of metastasis in other cancers, Dr. Mohla explained, including a recent one that implicated Rho-C in metastatic melanoma.
As for Twist, while research into how it functions in metastasis is still preliminary, Dr. Yang said the available evidence does point to potential diagnostic and treatment applications.