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