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Blockade of Autocrine TGF-ß Signaling Inhibits Stem Cell Phenotype, Survival, and Metastasis of Murine Breast Cancer Cells

Zhao Liu, Abhik Bandyopadhyay, Robert W. Nichols, Long Wang, Andrew P. Hinck, Shui Wang and Lu-Zhe Sun

Transforming growth factor beta (TGF-β) signaling has been implicated in driving tumor progression and metastasis by inducing stem cell-like features in some human cancer cell lines. In this study, we have utilized a novel murine cell line NMuMG-ST, which acquired cancer stem cell (CSC) phenotypes during spontaneous transformation of the untransformed murine mammary cell line NMuMG, to investigate the role of autocrine TGF-β signaling in regulating their survival, metastatic ability, and the maintenance of cancer stem cell characteristics. We have retrovirally transduced a dominant-negative TGF-β type II receptor (DNRII) into the NMuMG-ST cell to abrogate autocrine TGF-β signaling. The expression of DNRII reduced TGF-β sensitivity of the NMuMG-ST cells in various cell-based assays. The blockade of autocrine TGF-β signaling reduced the ability of the cell to grow anchorageindependently and to resist serum deprivation-induced apoptosis. These phenotypes were associated with reduced levels of active and phosphorylated AKT and ERK, and Gli1 expression suggesting that these pathways contribute to the growth and survival of this model system. More interestingly, the abrogation of autocrine TGF-β signaling also led to the attenuation of several features associated with mammary stem cells including epithelial-mesenchymal transition, mammosphere formation, and expression of stem cell markers. When xenografted in athymic nude mice, the DNRII cells were also found to undergo apoptosis and induced significantly lower lung metastasis burden than the control cells even though they formed similar size of xenograft tumors. Thus, our results indicate that autocrine TGF-β signaling is involved in the maintenance and survival of stem-like cell population resulting in the enhanced metastatic ability of the murine breast cancer cells.