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@article{lam2017a,
 abstract = {mTORC1 hyperactivation drives the multi-organ hamartomatous disease tuberous sclerosis complex (TSC). Rapamycin inhibits mTORC1, inducing partial tumor responses; however, the tumors regrow following treatment cessation. We discovered that the oncogenic miRNA, miR-21, is increased in Tsc2-deficient cells and, surprisingly, further increased by rapamycin. To determine the impact of miR-21 in TSC, we inhibited miR-21 in vitro. miR-21 inhibition significantly repressed the tumorigenic potential of Tsc2-deficient cells and increased apoptosis sensitivity. Tsc2-deficient cells' clonogenic and anchorage independent growth were reduced by approximately 50% (p$<$0.01) and approximately 75% (p$<$0.0001), respectively, and combined rapamycin treatment decreased soft agar growth by approximately 90% (p$<$0.0001). miR-21 inhibition also increased sensitivity to apoptosis. Through a network biology-driven integration of RNAseq data, we discovered that miR-21 promotes mitochondrial adaptation and homeostasis in Tsc2-deficient cells. miR-21 inhibition reduced mitochondrial polarization and function in Tsc2-deficient cells, with and without co-treatment with rapamycin. Importantly, miR-21 inhibition limited Tsc2-deficient tumor growth in vivo, reducing tumor size by approximately 3-fold (p$<$0.0001). When combined with rapamcyin, miR-21 inhibition showed even more striking efficacy, both during treatment and after treatment cessation, with a 4-fold increase in median survival following rapamycin cessation (p=0.0008). We conclude that miR-21 promotes mTORC1-driven tumorigenesis via a mechanism that involves the mitochondria, and that miR-21 is a potential therapeutic target for TSC-associated hamartomas and other mTORC1-driven tumors, with the potential for synergistic efficacy when combined with rapalogs.},
 author = {<NAME>. and <NAME> <NAME>. and <NAME>. and <NAME>. and <NAME>. and <NAME>. and <NAME>. and <NAME>. and <NAME>. and <NAME>. and <NAME> <NAME> <NAME> <NAME>.},
 doi = {10.18632/oncotarget.19947},
 file = {/Users/will/Dropbox (Partners HealthCare)/zotero-library/2017_lam_rapamycin-induced_mir-21_promotes_mitochondrial_homeostasis_and_adaptation_in.pdf},
 issn = {1949-2553 (Electronic) 1949-2553 (Linking)},
 journal = {Oncotarget},
 keywords = {miR-21,mitochondria,mTORC1,rapamycin,tuberous sclerosis complex},
 month = {September},
 number = {39},
 pages = {64714--64727},
 pmcid = {PMC5630288},
 title = {Rapamycin-Induced miR-21 Promotes Mitochondrial Homeostasis and Adaptation in mTORC1 Activated Cells},
 volume = {8},
 year = {2017}
}

