title: Curcumin inhibits breast cancer stem cell migration by amplifying the E-cadherin/β-catenin negative feedback loop.
abstract: BACKGROUND
  The existence of cancer stem cells (CSCs) has been associated with tumor initiation, therapy resistance, tumor relapse, angiogenesis, and metastasis. Curcumin, a plant ployphenol, has several anti-tumor effects and has been shown to target CSCs. Here, we aimed at evaluating (i) the mechanisms underlying the aggravated migration potential of breast CSCs (bCSCs) and (ii) the effects of curcumin in modulating the same.
  
  
  METHODS
  The migratory behavior of MCF-7 bCSCs was assessed by using cell adhesion, spreading, transwell migration, and three-dimensional invasion assays. Stem cell characteristics were studied by using flow cytometry. The effects of curcumin on bCSCs were deciphered by cell viability assay, Western blotting, confocal microscopy, and small interfering RNA (siRNA)-mediated gene silencing. Evaluations of samples of patients with breast cancer were performed by using immunohistochemistry and flow cytometry.
  
  
  RESULTS
  Here, we report that bCSCs are endowed with aggravated migration property due to the inherent suppression of the tumor suppressor, E-cadherin, which is restored by curcumin. A search for the underlying mechanism revealed that, in bCSCs, higher nuclear translocation of beta-catenin (i) decreases E-cadherin/beta-catenin complex formation and membrane retention of beta-catenin, (ii) upregulates the expression of its epithelial-mesenchymal transition (EMT)-promoting target genes (including Slug), and thereby (iii) downregulates E-cadherin transcription to subsequently promote EMT and migration of these bCSCs. In contrast, curcumin inhibits beta-catenin nuclear translocation, thus impeding trans-activation of Slug. As a consequence, E-cadherin expression is restored, thereby increasing E-cadherin/beta-catenin complex formation and cytosolic retention of more beta-catenin to finally suppress EMT and migration of bCSCs.
  
  
  CONCLUSIONS
  Cumulatively, our findings disclose that curcumin inhibits bCSC migration by amplifying E-cadherin/beta-catenin negative feedback loop.
authors.forename: Shravanti
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Minakshi
authors.initials: M
authors.lastname: Mazumdar
authors.forename: Samik
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Argha
authors.initials: A
authors.lastname: Manna
authors.forename: Shilpi
authors.initials: S
authors.lastname: Saha
authors.forename: Poulami
authors.initials: P
authors.lastname: Khan
authors.forename: Pushpak
authors.initials: P
authors.lastname: Bhattacharjee
authors.forename: Deblina
authors.initials: D
authors.lastname: Guha
authors.forename: Arghya
authors.initials: A
authors.lastname: Adhikary
authors.forename: Sanhita
authors.initials: S
authors.lastname: Mukhjerjee
authors.forename: Tanya
authors.initials: T
authors.lastname: Das
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D015820:Cadherins; D051176:beta Catenin; D003474:Curcumin