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Abstract
The mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and proliferation. Recent studies have suggested that constitutive activation of mTORC1 in normal cells could lead to malignant tumor development in several tissues. However, the mechanisms of mTORC1 hyperactivation to promote the growth and metastasis of breast or other cancers are still not well characterized. Here, using a new inducible deletion system, we show that deletion of Tsc1 in mouse primary mammary tumor cells, either before or after their transplantation, significantly increased their growth in vivo. The increase in tumor growth was completely rescued by rapamycin treatment, suggesting a major contribution from mTORC1 hyperactivation. Interestingly, glucose starvation-induced autophagy, but not amino acid starvation-induced autophagy, was increased significantly in Tsc1-null tumor cells. Further analysis of these cells also showed an increased Akt activation but no significant changes in Erk signaling. Together, these results provide insights into the mechanism by which hyperactivation of mTORC1 promotes breast cancer progression through increasing autophagy and Akt activation in vivo.
Highlights
TSC1 is a negative regulator for mammalian target of rapamycin complex 1 (mTORC1) that is implicated in cancer
To study the role of Tsc1 and mTOR signaling in breast cancer cells directly, we generated primary mammary tumor cells whose Tsc1 gene can be deleted in an inducible manner
By generating and analyzing a unique model with inducible deletion of Tsc1 in mouse primary mammary tumor cells, we show here a novel mechanism showing that deletion of Tsc1 and consequent activation of mTORC1 promotes mammary tumor growth through increased autophagy under glucose starvation conditions as well as increased Akt activation
Summary
TSC1 is a negative regulator for mTORC1 that is implicated in cancer. Results: mTORC1 activation by TSC1 deletion promotes mammary tumor growth through increasing autophagy and Akt activation of tumor cells. Glucose starvation-induced autophagy, but not amino acid starvation-induced autophagy, was increased significantly in Tsc1-null tumor cells Further analysis of these cells showed an increased Akt activation but no significant changes in Erk signaling. Together, these results provide insights into the mechanism by which hyperactivation of mTORC1 promotes breast cancer progression through increasing autophagy and Akt activation in vivo. MTORC1 contains the catalytic subunit mTOR and its binding partners mLST8/GL, PRAS40, and Raptor, which have been well documented to promote the growth and proliferation of a variety of cells through the phosphorylation of two main regulators of mRNA translation and ribosome biogenesis, ribosomal S6 kinase (S6K) and eukaryotic initiation factor 4E binding protein 1 (4EBP1) [4, 6], a multitude of other targets have been suggested in recent studies [7]. We showed that Tsc deletion increased glucose starvation-induced autophagy as well as Akt activation, which could promote tumor cell survival and contribute to the increased tumor growth in vivo
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