title: Targeting Met and Notch in the Lfng-deficient, Met-amplified triple-negative breast cancer.
abstract: Triple negative breast cancer (TNBC) accounts for 15-20% of breast carcinomas and represents one of the most aggressive forms of this disease. Basal and claudin-low are the two main molecular subtypes among TNBCs. We previously reported that deletion of Lfng in mouse mammary gland caused deregulated Notch activation and induced basal-like and claudin-low tumors with co-selection for Met amplification. In human breast cancers, the vast majority of basal tumors and a subset of claudin-low tumors show reduced Lfng expression. Elevated Met expression and activation is associated with basal as well as claudin-low subtypes. To examine roles of Met and Notch in TNBC cells, we established two cell lines that harbor Met amplification as well as Lfng deletion, and possess features of basal and claudin-low breast cancer subtypes. Pharmacological inhibition of Met not only suppressed cell growth, tumorsphere and colony formation, but also reversed epithelial-to-mesenchymal transition and inhibited cell migration in both cell lines. In contrast, inhibition of Notch signaling using a γ-secretase inhibitor (GSI) only suppressed colony formation. Interestingly, GSI had no effect as single agent, but exerted a synergistic effect with Met inhibitor, on cell growth in 2D culture. We found that inhibition of Met resulted in downregulation of Dll ligands and upregulation of Jagged ligands, leading to differential modulation of Notch signaling. Our results suggest that combination targeting of Met and Notch may prove beneficial for TNBC patients with Met overexpression and Notch hyperactivation.
authors.affiliation: Cancer Institute; University of Mississippi Medical Center; Jackson, MS USA.
authors.forename: Shubing
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Cancer Institute; University of Mississippi Medical Center; Jackson, MS USA.
authors.forename: Wen-cheng
authors.initials: WC
authors.lastname: Chung
authors.affiliation: Cancer Institute; University of Mississippi Medical Center; Jackson, MS USA; Department of Pharmacology and Toxicology; University of Mississippi Medical Center; Jackson, MS USA.
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
authors.affiliation: Cancer Institute; University of Mississippi Medical Center; Jackson, MS USA; Department of Neurobiology and Anatomical Sciences; University of Mississippi Medical Center; Jackson, MS USA.
authors.forename: Keli
authors.initials: K
authors.lastname: Xu
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015870:Gene Expression; D016695:Glycosyltransferases / Q000235:genetics*; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D010879:Piperazines / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); C554093:3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid; D001555:Benzene Derivatives; D007211:Indoles; D010879:Piperazines; D011422:Propionates; D051880:Receptors, Notch; D013449:Sulfonamides; D013450:Sulfones; D016695:Glycosyltransferases; C498392:Lfng protein, mouse; D019859:Proto-Oncogene Proteins c-met; D053829:Amyloid Precursor Protein Secretases
keywords: Lfng; Met; Met inhibitor; Notch; basal-like breast cancer; claudin-low breast cancer; epithelial-to-mesenchymal transition; triple negative breast cancer; γ-secretase inhibitor