A Novel Role for Plakoglobin in Regulating Critical Stem Cell and Cancer Cell Functions Revealed by Using Pluripotent Stem Cells to Identify Embryonic Mechanisms Mediating Cancer Aggressiveness

Accumulating evidence has shown the presence of embryonic stem cell programs in cancer cells that contribute to aggressive malignancy. To strategically identify relevant embryonic-like mechanisms exploited by cancer cells, we performed mass spectrometry of the cell surface proteome of human induced pluripotent stem cells (iPS cells) and breast cancer cells to find surface molecules shared by both cell types. Plakoglobin was identified as a target of high significance for its reported importance in circulating tumor cell (CTC) clusters of breast cancer. Moreover, as a homolog of β-catenin, plakoglobin has also been described to be involved in signaling pathways essential for both cancer cells and stem cells. However, how plakoglobin affects cancer aggressiveness, and whether it plays an important role in maintaining stem cell functions, remains unclear. Here, we report that plakoglobin is overexpressed in cancer stem cell populations of breast cancer, as well as iPS cells compared to their parental somatic cells. Overexpression of plakoglobin resulted in elevated cell-cell adhesion, as well as motility, in both breast cancer cells and iPS cells. Furthermore, overexpression of plakoglobin in both cell types led to increased resistance to apoptosis by alleviating Rho/ROCK activity through increased cell adhesion. Our findings establish a novel role for plakoglobin in regulating cell behavior and survival in cancer and stem cells, and suggest that an embryonic-like mechanism of plakoglobin may be exploited by cancer cells to provide a survival advantage to overcome anoikis during metastasis. The paralleled studies in iPS cells provide insights into future mechanistic inquiries of tumor progression, and thus new potential avenues for therapeutic target discoveries towards the long-term goals of preventing cancer metastasis and relapse.