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Yu Jane , Henske Elizabeth Petri
Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homolog enriched in brain
Cancer Research. 2006 ;66(19) :9461-9466
PMID: AN 2006:1025075   
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Abstract
Inhibitors of the mammalian target of rapamycin (mTOR) are currently in clin. trials for the treatment of breast cancer. The mechanisms through which mTOR are activated in breast cancer and the relationship of mTOR activation to steroid hormones, such as estrogen, that are known to influence breast cancer pathogenesis, are not yet understood. Using MCF-7 cells as a model, we found that 17-b estradiol (E2) rapidly increased the phosphorylation of downstream targets of mTOR: p70 ribosomal protein S6 kinase, ribosomal protein S6, and eukaryotic initiation factor 4E-binding protein 1. The phosphoinositide-3-kinase inhibitor, wortmannin, and the mTOR inhibitor, rapamycin, blocked E2-induced activation of p70 ribosomal protein S6 kinase. We hypothesized that tuberin and the small GTPase Ras homolog enriched in brain (Rheb), regulators of the mTOR pathway, mediate E2-induced activation of mTOR. Consistent with this hypothesis, E2 rapidly (within 5 min) stimulated tuberin phosphorylation at T1462, a site at which Akt phosphorylates and inactivates tuberin. E2 also rapidly decreased the inactive, GDP-bound form of Rheb. Finally, we found that small interfering RNA down-regulation of endogenous Rheb blocked the E2-stimulated proliferation of MCF-7 cells, demonstrating that Rheb is a key determinant of E2-dependent cell growth. Taken together, these data reveal that the TSC/Rheb/mTOR pathway plays a crit. role in the regulation of E2-induced proliferation, and highlight Rheb as a novel mol. target for breast cancer therapy. [on SciFinder (R)]
Notes
CAN 145:348811 2-4 Mammalian Hormones Department of Medical Oncology,Fox Chase Cancer Center,Philadelphia,PA,USA. Journal 0008-5472 written in English. 50-28-2 (Estradiol); 90698-26-3D (p70 Ribosomal S6 kinase); 137632-07-6D (p44 MAP kinase); 137632-08-7 (p42 MAP kinase); 148640-14-6D (Protein kinase akt); 171715-28-9 (Mammalian target of rapamycin) Role: BSU (Biological study, unclassified), BIOL (Biological study) (estrogen-induced activation of TSC/Rheb/mTOR/MAP/Akt kinase pathway in breast cancer cell proliferation)