title: Tsc1 deficiency impairs mammary development in mice by suppression of AKT, nuclear ERα, and cell-cycle-driving proteins.
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.
authors.affiliation: Department of Histology and Embryology, Southern Medical University, Guangzhou, China.
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Department of Oncology, Nanfang Hospital, Postal code 510515, Guangzhou, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Oncology, Nanfang Hospital, Postal code 510515, Guangzhou, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Ou
authors.affiliation: Academy of Orthopedics of Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.affiliation: Academy of Orthopedics of Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
authors.affiliation: Department of Orthopedics, The First People Hospital of Chen Zhou , University of South China, Hunan Province, China.
authors.forename: Zhenshu
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Cuilan
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Bioinformatics, School of Basic Medical Science, Southern Medical University, Guangzhou, China.
authors.forename: Yongchun
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Histology and Embryology, Southern Medical University, Guangzhou, China.|Key Laboratory of Tissue Construction and Detection of Guangdong Province, Guangzhou, China.|Institute of Bone Biology, Academy of Orthopedics, Guangzhou,China.
authors.forename: Jiasong
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D047628:Estrogen Receptor alpha; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus