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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.

Tsc1 deficiency impairs mammary development in mice by suppression of AKT, nuclear ERα and cell-cycle-driving proteins