Abstract
Loss of Tsc1/Tsc2 results in excess cell growth that eventually forms hamartoma in multiple organs. Our study using a mouse model with Tsc1 conditionally knockout in mammary epithelium showed that Tsc1 deficiency impaired mammary development. Phosphorylated S6 was up-regulated in Tsc1−/− mammary epithelium, which could be reversed by rapamycin, suggesting that mTORC1 was hyperactivated in Tsc1−/− mammary epithelium. The mTORC1 inhibitor rapamycin restored the development of Tsc1−/− mammary glands whereas suppressed the development of Tsc1wt/wt mammary glands, indicating that a modest activation of mTORC1 is critical for mammary development. Phosphorylated PDK1 and AKT, nuclear ERα, nuclear IRS-1, SGK3, and cell cycle regulators such as Cyclin D1, Cyclin E, CDK2, CDK4 and their target pRB were all apparently down-regulated in Tsc1−/− mammary glands, which could be reversed by rapamycin, suggesting that suppression of AKT by hyperactivation of mTORC1, inhibition on nuclear ERα signaling, and down-regulation of cell-cycle-driving proteins play important roles in the retarded mammary development induced by Tsc1 deletion. This study demonstrated for the first time the in vivo role of Tsc1 in pubertal mammary development of mice, and revealed that loss of Tsc1 does not necessarily lead to tissue hyperplasia.
Highlights
Containing mTOR, regulatory protein of mTOR (Raptor), PRAS40 and mLST8, is directly activated by a small GTPase called Ras-homology enriched in brain (Rheb), whose activation is controlled by TSC1/TSC2 complex[7,9]
It was evident that the mammary ductal tree was less developed in Tsc1−/− mammary glands than it was in the control Tsc1wt/wt mammary glands (Fig. 1a,b), confirmed by quantitative comparison of numbers of terminal end buds (TEBs) and mammary branches between Tsc1−/− and Tsc1wt/wt mammary glands (Fig. 1c,d)
We found that phosphorylation of S6 (p-S6), a downstream target of mTORC1, was far more enhanced in Tsc1−/− mammary glands than it was in the Tsc1wt/wt glands (Fig. 2a–d), indicating that mTORC1 of the mammary epithelium is sustained activated by Tsc[1] knockout
Summary
Containing mTOR, regulatory protein of mTOR (Raptor), PRAS40 and mLST8, is directly activated by a small GTPase called Ras-homology enriched in brain (Rheb), whose activation is controlled by TSC1/TSC2 complex[7,9]. When mTORC1 is activated, S6K, one of the mTORC1 downstream target, will disrupt the interaction of insulin receptor substrate-1 (IRS-1) with insulin receptors[12], leading to a blockage in insulin signaling to AKT13,14, and suppress the AKT activity. Such negative feedback regulation on AKT by mTORC1 surely plays a vital role in controlling proper cell growth and proliferation. Tissue and organ development demands appropriate cell growth, proliferation and apoptosis, where mTORC1 signaling exert a critical role. This study indicated that a modest mTORC1 activity was critical for pubertal mammary gland development in mice
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