HER2-mediated GLI2 stabilization promotes anoikis resistance and metastasis of breast cancer cells

Breast cancer metastasis is a multi-step process and requires cells to overcome anoikis. Anoikis is defined as cell death that occurs due to loss of cell adhesion. During the course of cancer progression, tumor cells acquire resistance to anoikis. However, mechanisms of anoikis resistance are not clear. Human epidermal growth receptor 2 (HER2) overexpressing breast tumors are known to be highly aggressive and metastatic. The mechanisms correlating HER2 with metastasis are poorly understood. We observed increased anoikis resistance in HER2 overexpressing breast cancer cells. In addition, we identified that HER2 overexpression was also associated with increased sonic hedgehog (SHH) signaling especially GLI2, and that inhibition of SHH pathway suppressed anoikis resistance. GSK3 beta is known to facilitate proteasome-mediated degradation of GLI2. Moreover, we observed that silencing of GLI2 resulted in reduced migration and invasion of HER2 over expressing cells. Anoikis resistant HER2 overexpressing cells also showed increased rate and extent of metastasis in vivo, as compared to wild type anoikis resistant cells. Taken together, this study indicates a novel role of HER2/GSK3 beta/GLI2 axis in anoikis resistance and metastasis, and that GLI2 could be a potential target for anticancer therapies.