title: Alcohol promotes breast cancer cell invasion by regulating the Nm23-ITGA5 pathway.
abstract: BACKGROUND
  Alcohol consumption is an established risk factor for breast cancer metastasis. Yet, the mechanism by which alcohol promotes breast cancer metastases is unknown. The ability of cancer cells to invade through tissue barriers (such as basement membrane and interstitial stroma) is an essential step towards establishing cancer metastasis. In the present study, we identify and examine the roles of two genes, Nm23 and ITGA5, in alcohol-induced breast cancer cell invasion.
  
  
  METHODS
  Human breast cancer T47D cells were treated with ethanol at various concentrations. Boyden chamber invasion assays were used to measure cellular invasive ability. The mRNA expression level of metastasis suppressor genes including Nm23 was determined by qRT-PCR. ITGA5 was identified using a qRT-PCR array of 84 genes important for cell-cell and cell-extracellular matrix interactions. Nm23 overexpression in addition to Nm23- and ITGA5 knock-down were used to determine the role of the Nm23-ITGA5 pathway on cellular invasive ability of T47D cells. Protein expression levels were verified by Western blot.
  
  
  RESULTS
  Alcohol increased the invasive ability of human breast cancer T47D cells in a dose-dependent manner through the suppression of the Nm23 metastatic suppressor gene. In turn, Nm23 down-regulation increased expression of fibronectin receptor subunit ITGA5, which subsequently led to increased cellular invasion. Moreover, Nm23 overexpression was effective in suppressing the effects of alcohol on cell invasion. In addition, we show that the effects of alcohol on invasion were also inhibited by knock-down of ITGA5.
  
  
  CONCLUSIONS
  Our results suggest that the Nm23-ITGA5 pathway plays a critical role in alcohol-induced breast cancer cell invasion. Thus, regulation of this pathway may potentially be used to prevent the establishment of alcohol-promoted metastases in human breast cancers.
authors.affiliation: Institute for Cell and Molecular Biology, University of Texas, Austin, TX, USA.
authors.forename: Amy W
authors.initials: AW
authors.lastname: Wong
authors.forename: Qiwei X
authors.initials: QX
authors.lastname: Paulson
authors.forename: Jina
authors.initials: J
authors.lastname: Hong
authors.forename: Renee E
authors.initials: RE
authors.lastname: Stubbins
authors.forename: Karen
authors.initials: K
authors.lastname: Poh
authors.forename: Emily
authors.initials: E
authors.lastname: Schrader
authors.forename: Nomeli P
authors.initials: NP
authors.lastname: Nunez
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D039564:Integrin alphaV / Q000235:genetics* / Q000378:metabolism; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D002492:Central Nervous System Depressants; D039564:Integrin alphaV; D054778:NM23 Nucleoside Diphosphate Kinases; D012333:RNA, Messenger; D000431:Ethanol; C517938:NME1 protein, human