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 Tsc1(wt/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.