title: Metformin attenuates transforming growth factor beta (TGF-β) mediated oncogenesis in mesenchymal stem-like/claudin-low triple negative breast cancer.
abstract: Mesenchymal stem-like/claudin-low (MSL/CL) breast cancers are highly aggressive, express low cell-cell adhesion cluster containing claudins (CLDN3/CLDN4/CLDN7) with enrichment of epithelial-to-mesenchymal transition (EMT), immunomodulatory, and transforming growth factor-β (TGF-β) genes. We examined the biological, molecular and prognostic impact of TGF-β upregulation and/or inhibition using in vivo and in vitro methods. Using publically available breast cancer gene expression databases, we show that upregulation and enrichment of a TGF-β gene signature is most frequent in MSL/CL breast cancers and is associated with a worse outcome. Using several MSL/CL breast cancer cell lines, we show that TGF-β elicits significant increases in cellular proliferation, migration, invasion, and motility, whereas these effects can be abrogated by a specific inhibitor against TGF-β receptor I and the anti-diabetic agent metformin, alone or in combination. Prior reports from our lab show that TNBC is exquisitely sensitive to metformin treatment. Mechanistically, metformin blocks endogenous activation of Smad2 and Smad3 and dampens TGF-β-mediated activation of Smad2, Smad3, and ID1 both at the transcriptional and translational level. We report the use of ID1 and ID3 as clinical surrogate markers, where high expression of these TGF-β target genes was correlated to poor prognosis in claudin-low patients. Given TGF-β's role in tumorigenesis and immunomodulation, blockade of this pathway using direct kinase inhibitors or more broadly acting inhibitors may dampen or abolish pro-carcinogenic and metastatic signaling in patients with MCL/CL TNBC. Metformin therapy (with or without other agents) may be a heretofore unrecognized approach to reduce the oncogenic activities associated with TGF-β mediated oncogenesis.
authors.affiliation: a Department of Pathology , University of Colorado , Anschutz Medical Campus Mail Stop B216, 12631 East 17th Ave, Room 2215A, Aurora , CO , USA.
authors.forename: Reema
authors.initials: R
authors.lastname: Wahdan-Alaswad
authors.affiliation: b Department of Pathology , Virginia Commonwealth University , 1101 E Marshall St., PO Box 980662, Richmond VA , USA.
authors.forename: J Chuck
authors.initials: JC
authors.lastname: Harrell
authors.affiliation: a Department of Pathology , University of Colorado , Anschutz Medical Campus Mail Stop B216, 12631 East 17th Ave, Room 2215A, Aurora , CO , USA.
authors.forename: Zeying
authors.initials: Z
authors.lastname: Fan
authors.affiliation: a Department of Pathology , University of Colorado , Anschutz Medical Campus Mail Stop B216, 12631 East 17th Ave, Room 2215A, Aurora , CO , USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Edgerton
authors.affiliation: a Department of Pathology , University of Colorado , Anschutz Medical Campus Mail Stop B216, 12631 East 17th Ave, Room 2215A, Aurora , CO , USA.
authors.forename: Bolin
authors.initials: B
authors.lastname: Liu
authors.affiliation: a Department of Pathology , University of Colorado , Anschutz Medical Campus Mail Stop B216, 12631 East 17th Ave, Room 2215A, Aurora , CO , USA.
authors.forename: Ann D
authors.initials: AD
authors.lastname: Thor
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057167:Claudins / Q000378:metabolism*; D018572:Disease-Free Survival; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055879:Gene Knock-In Techniques; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008687:Metformin / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D014408:Biomarkers, Tumor; D057167:Claudins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D008687:Metformin
keywords: Breast cancer; TGF-β; claudin-low; mesenchymal; mesenchymal stem-like; metformin; triple negative breast cancer (TNBC)