title: Simvastatin prevents triple-negative breast cancer metastasis in pre-clinical models through regulation of FOXO3a.
abstract: We previously reported using statins was correlated with improved metastasis-free survival in aggressive breast cancer. The purpose of this study was to examine the effect of statins on metastatic colonization by triple-negative breast cancer (TNBC) cells. TNBC cell lines were treated with simvastatin and then studied for cell cycle progression and proliferation in vitro, and metastasis formation in vivo, following injection of statin-treated cells. Reverse-phase protein assay (RPPA) analysis was performed on statin-treated and control breast cancer cells. RNA interference targeting FOXO3a was used to measure the impact of simvastatin on FOXO3a-expressing cells. The prognostic value of FOXO3a mRNA expression was examined in eight public breast cancer gene expression datasets including 1479 patients. Simvastatin increased G1/S-phase arrest of the cell cycle and inhibited both proliferation and migration of TNBC cells in vitro. In vitro pre-treatment and in vivo treatment with simvastatin reduced metastases. Phosphorylated FOXO3a was downregulated after simvastatin treatment in (RPPA) analysis. Ectopic expression of FOXO3a enhanced mammosphere formation and migratory capacity in vitro. Knockdown of FOXO3a attenuated the effect of simvastatin on mammosphere formation and migration. Analysis of public gene expression data demonstrates FOXO3a mRNA downregulation was independently associated with shorter metastasis-free survival in all breast cancers, as well as in TNBC breast cancers. Simvastatin inhibits in vitro endpoints associated with metastasis through a FOXO3a mechanism and reduced metastasis formation in vivo. FOXO3a expression is prognostic for metastasis formation in patient data. Further investigation of simvastatin as a cancer therapy is warranted.
authors.affiliation: MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wolfe
authors.affiliation: MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA.
authors.forename: Bisrat G
authors.initials: BG
authors.lastname: Debeb
authors.affiliation: MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Lacerda
authors.affiliation: MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Larson
authors.affiliation: MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Bambhroliya
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xuelin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Molecular Oncology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Department of Molecular Oncology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Department of Molecular Oncology, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.affiliation: Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Van Laere
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA.
authors.forename: Parmeswaran
authors.initials: P
authors.lastname: Diagaradjan
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Ruffell
authors.affiliation: Departments of Chemistry and Bioengineering, Rice University, Houston, TX, USA.
authors.forename: Nicholaus J
authors.initials: NJ
authors.lastname: Trenton
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Khoi
authors.initials: K
authors.lastname: Chu
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Hittelman
authors.affiliation: Departments of Chemistry and Bioengineering, Rice University, Houston, TX, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Diehl
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Ilya
authors.initials: I
authors.lastname: Levental
authors.affiliation: MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
authors.affiliation: MD Anderson Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. wwoodward@mdanderson.org.|Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1202, Houston, TX, 77030, USA. wwoodward@mdanderson.org.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Woodward
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D016513:Mice, SCID; D008875:Middle Aged; D009362:Neoplasm Metastasis; D019821:Simvastatin / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin
keywords: FOXO3a; Metastasis; Simvastatin; Triple-negative breast cancer