"Overexpression of 14-3-3?¶ is the catalyst for a molecular pathway that strips E-cadherin from the cells, setting the cells loose from each other," Yu said. These cells also change in appearance from blunt normal breast duct cells to a narrow spindle shape characteristic of a mesenchymal-like cell.

Double overexpression reduces survival time

Epithelial cells line an organ or its cavities and are generally immobile. Mesenchymal cells are mobile and can differentiate into many different cell types, for example, to repair injury. Epithelial-mesenchymal transition is known to repress E-cadherin, decrease cell-cell adhesion and increase a cell's capacity to move. An estimated 80 percent of all solid tumors are carcinomas, cancers of the epithelial tissue.

Mice injected with a breast cancer cell line with both proteins overexpressed had three times the metastasis as mice with a control cancer cell line.

The researchers examined 107 invasive breast cancer cases and found that 23 of the cancers overexpressed both proteins. Those patients also had significantly shorter survival times due to metastasis-related deaths than those whose tumors expressed one or neither of the proteins.

Overexpressed 14-3-3?¶, the team showed, interacts with and stabilizes the receptor protein T??R1, which activates smad2/3 and moves them into the cell nucleus, where they in turn increase expression of ZFHX1B, which then represses expression of the adhesion protein E-cadherin.

Yu said that it will be very challenging to target 14-3-3?¶ by drugs because it also regulates other important proteins in normal cellular processes. The downstream components such as T??R1 can be targeted with drugs that are under clinical trials.

Source: University of Texas M. D. Anderson Cancer Center