title: Bromoenol Lactone Attenuates Nicotine-Induced Breast Cancer Cell Proliferation and Migration.
abstract: OBJECTIVE
  Calcium independent group VIA phospholipase A2 (iPLA2β) and Matrix Metalloproteinase-9 (MMP-9) are upregulated in many disease states; their involvement with cancer cell migration has been a recent subject for study. Further, the molecular mechanisms mediating nicotine-induced breast cancer cell progression have not been fully investigated. This study aims to investigate whether iPLA2β mediates nicotine-induced breast cancer cell proliferation and migration through both in-vitro and in-vivo techniques. Subsequently, the ability of Bromoenol Lactone (BEL) to attenuate the severity of nicotine-induced breast cancer was examined.
  
  
  RESULTS
  We found that BEL significantly attenuated both basal and nicotine-induced 4T1 breast cancer cell proliferation, via an MTT proliferation assay. Breast cancer cell migration was examined by both a scratch and transwell assay, in which, BEL was found to significantly decrease both basal and nicotine-induced migration. Additionally, nicotine-induced MMP-9 expression was found to be mediated in an iPLA2β dependent manner. These results suggest that iPLA2β plays a critical role in mediating both basal and nicotine-induced breast cancer cell proliferation and migration in-vitro. In an in-vivo mouse breast cancer model, BEL treatment was found to significantly reduce both basal (p<0.05) and nicotine-induced tumor growth (p<0.01). Immunohistochemical analysis showed BEL decreased nicotine-induced MMP-9, HIF-1alpha, and CD31 tumor tissue expression. Subsequently, BEL was observed to reduce nicotine-induced lung metastasis.
  
  
  CONCLUSIONS
  The present study indicates that nicotine-induced migration is mediated by MMP-9 production in an iPLA2β dependent manner. Our data suggests that BEL is a possible chemotherapeutic agent as it was found to reduce both nicotine-induced breast cancer tumor growth and lung metastasis.
authors.affiliation: Department of Biology, Eastern Kentucky University, Richmond, KY, 40475, United States of America.
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Calderon
authors.affiliation: Department of Physiology, Hebei University Health Science Center, Hebei, 071000, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Biology, Eastern Kentucky University, Richmond, KY, 40475, United States of America.
authors.forename: Nova
authors.initials: N
authors.lastname: Arnold
authors.affiliation: Department of Biology, Eastern Kentucky University, Richmond, KY, 40475, United States of America.
authors.forename: Bethany
authors.initials: B
authors.lastname: Breakall
authors.affiliation: Department of Biology, Eastern Kentucky University, Richmond, KY, 40475, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Rollins
authors.affiliation: Department of Chemistry, Eastern Kentucky University, Richmond, KY, 40475, United States of America.
authors.forename: Margaret
authors.initials: M
authors.lastname: Ndinguri
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000037:antagonists & inhibitors* / Q000633:toxicity; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000494:pharmacology*; D009538:Nicotine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology*; D015398:Signal Transduction; D015533:Transcriptional Activation; D023041:Xenograft Model Antitumor Assays
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009281:Naphthalenes; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011753:Pyrones; D009538:Nicotine; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; D020780:Matrix Metalloproteinase 9