title: Novel Aryl Hydrocarbon Receptor Agonist Suppresses Migration and Invasion of Breast Cancer Cells.
abstract: BACKGROUND
  Despite the remarkable progress to fight against breast cancer, metastasis remains the dominant cause of treatment failure and recurrence. Therefore, control of invasiveness potential of breast cancer cells is crucial. Accumulating evidences suggest Aryl hydrocarbon receptor (Ahr), a helix-loop-helix transcription factor, as a promising target to control migration and invasion in breast cancer cells. Thus, an Ahr-based exploration was performed to identify a new Ahr agonist with inhibitory potentials on cancer cell motility.
  
  
  METHODS
  For prediction of potential interactions between Ahr and candidate molecules, bioinformatics analysis was carried out. The interaction of the selected ligand with Ahr and its effects on migration and invasion were examined in vitro using the MDA-MB-231 and T47D cell lines. The silencing RNAs were transfected into cells by electroporation. Expressions of microRNAs (miRNAs) and coding genes were quantified by real-time PCR, and the protein levels were detected by western blot.
  
  
  RESULTS
  The in silico and in vitro results identified Flavipin as a novel Ahr agonist. It induces formation of Ahr/Ahr nuclear translocator (Arnt) heterodimer to promote the expression of cytochrome P450 family 1 subfamily A member 1 (Cyp1a1). Migration and invasion of MDA-MB-231 and T47D cells were inhibited with Flavipin treatment in an Ahr-dependent fashion. Interestingly, Flavipin suppressed the pro-metastatic factor SRY-related HMG-box4 (Sox4) by inducing miR-212/132 cluster. Moreover, Flavipin inhibited growth and adhesion of both cell lines by suppressing gene expressions of B-cell lymphoma 2 (Bcl2) and integrinα4 (ITGA4).
  
  
  CONCLUSIONS
  Taken together, the results introduce Flavipin as a novel Ahr agonist, and provide first evidences on its inhibitory effects on cancer cell motility, suggesting Flavipin as a candidate to control cell invasiveness in breast cancer patients.
authors.affiliation: Biological Sciences Department, College of Science, King Faisal University, Hofuf Ahsaa, Saudi Arabia.
authors.forename: Hamza
authors.identifier: http://orcid.org/0000-0001-9230-3858
authors.initials: H
authors.lastname: Hanieh
authors.affiliation: Biomedical Department, College of Clinical Pharmacy, Hofuf Ahsaa, Saudi Arabia.|Biochemistry Department, College of Pharmacy Al-Azhar University Assiut, Egypt.
authors.forename: Omar
authors.initials: O
authors.lastname: Mohafez
authors.affiliation: Biological Sciences Department, College of Science, King Faisal University, Hofuf Ahsaa, Saudi Arabia.|Pondicherry Centre For Biological Sciences, Jawahar Nagar, Pondicherry, India.
authors.forename: Villianur Ibrahim
authors.initials: VI
authors.lastname: Hairul-Islam
authors.affiliation: Biological Sciences Department, College of Science, King Faisal University, Hofuf Ahsaa, Saudi Arabia.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alzahrani
authors.affiliation: Biological Sciences Department, College of Science, King Faisal University, Hofuf Ahsaa, Saudi Arabia.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Bani Ismail
authors.affiliation: Pondicherry Centre For Biological Sciences, Jawahar Nagar, Pondicherry, India.
authors.forename: Krishnaraj
authors.initials: K
authors.lastname: Thirugnanasambantham
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D009764:o-Phthalaldehyde / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000970:Antineoplastic Agents; D018336:Receptors, Aryl Hydrocarbon; C000621062:flavipin; D009764:o-Phthalaldehyde