Mutations of a single molecule play a key role in skin cancer, according to a new study. Researchers from the University of Chicago found that eliminating a molecule known to assist normal skin cells in making connections with one another profoundly changed the skin and caused it to exhibit a number of characteristics associated with squamous cell carcinoma, one of the two most common forms of skin cancer. "Although mutations of this molecule have been found in some types of cancer, it has generally been assumed that this was a late event following other mutations disrupting cell-cycle control," says lead investigator Elaine Fuchs. "We discovered, surprisingly, this component's loss appears to be a critical early event in the development of skin cancer." The team reported their findings Friday in the journal Cell.

Scientists had known that the organization of the skin's epidermal layer relies on intercellular structures known as adherens junctions and desmosomes. They also knew that the molecule alpha-catenin anchors the adherens junctions to the cell's scaffolding. But in order to fully understand how alpha-catenin functions, Fuchs and her colleagues created a line of mice in which the gene that makes alpha-catenin was absent in the skin cells. The results were unexpectedly dramatic. The epidermis of the knockout mice was thick and disorganized, and the skin's four usually distinct layers were distorted and difficult to distinguish. Moreover, the skin cells exhibited anomalies often associated with cancers.

"Loss of alpha-catenin alone seemed to cause at least a partial deregulation of cell-cycle control," Fuchs observes. "While one normally sees dividing cells only in the innermost layer, we saw them in multiple cell layers, including the ones near the skin surface that are normally in the process of dying. Cells often had more than one nucleus, an indication of defects in cell division." And when skin cells from the knockout mice were grown in cell culture, they proliferated more rapidly than did normal cells, to the point where they piled up on top of one another.

Such changes cannot be explained by alpha-catenin's role in intercellular connections alone, the team notes. Additional findings suggest that the molecule may also affect the signaling pathway that controls cell growth. "Alpha-catenin may be acting as a sensor, communicating changes in cell adhesion to the cell cycle regulatory machinery. This could account for why mutations of alpha-catenin can perturb the normal regulation of cell growth," Fuchs explains. "Taken together, our findings reveal a novel, hitherto unrecognized importance of this protein that goes beyond its role in intercellular adhesion, and which, when dysfunctional, may play a key role in this form of skin cancer."