Disabling of the erbB Pathway Followed by IFN-gamma Modifies Phenotype and Enhances Genotoxic Eradication of Breast Tumors

作者：Nagai Yasuhiro; Tsuchiya Hiromichi; Runkle E Aaron; Young Peter D; Ji Mei Q; Norton Larry; Drebin Jeffrey A; Zhang Hongtao; Greene Mark I^*

来源：Cell Reports, 2015, 12(12): 2049-2059.

DOI：10.1016/j.celrep.2015.08.044

Reversion of the malignant phenotype of erbB2-transformed cells can be driven by anti-erbB2/neu monoclonal antibodies (mAbs), which disrupt the receptor's kinase activity. We examined the biologic effects of IFN-gamma alone or after anti-erbB2/neu mAb treatment of erbB2-positive cells. IFN-gamma had no effect on its own. Treatment of the tumors with anti-erbB2/neu mAbs followed by IFN-gamma led to dramatic inhibition of tumor growth in vitro and in vivo with minimal mAb dosing. Sequential therapy enhanced the effects of chemotherapy. Moreover, IFN-gamma with mAb treatment of mice with IFN gamma R knockdown tumors did not demonstrate marked synergistic eradication effects, indicating an unexpected role of IFN-gamma on the tumor itself. Additionally, mAb and IFN-gamma treatment also induced immune host responses that enhanced tumor eradication. Biochemical analyses identified loss of Snail expression in tumor cells, reflecting diminution of tumor-stem-cell-like properties as a consequence of altered activity of GSK3-beta and KLF molecules.

• 出版日期2015-9-29