Influence of polyamines on in vitro and in vivo features of aggressive and metastatic behavior by human breast cancer cells.
Increased cellular activity of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine (PA) synthesis, is an independent adverse prognostic factor for overall survival in human breast cancer, thus suggesting an important role for PA in tumor progression. The experiments presented here were designed to investigate the role of PA in invasion and metastasis, using the highly aggressive MDA-MB-435 and MDA-MB-231 human breast cancer cell lines. Administration of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, significantly reduced, in a dose-dependent manner, the invasiveness in matrigel of both MDA-MB-435 and MDA-MB-231 cells by approximately 70%. DFMO treatment also inhibited (P < 0.0001) 'stellate' colony formation (an indicator of aggressive phenotype) by MDA-MB-435 cells plated in the matrigel outgrowth assay. Administration of DFMO (2% in drinking water) reduced the growth rate of both cell lines implanted orthotopically in nude mice. To evaluate metastasis while minimizing effects on proliferation, DFMO-treated mice were sacrificed later to allow their tumors to reach the same size of the tumors in the control mice. The most striking finding was that DFMO, while ineffective in reducing local invasion, nearly totally abolished (P = 0.0152) pulmonary metastasis in mice bearing MDA-MB-435 xenografts. These results support a role of PA in promoting breast cancer aggressiveness, particularly with regard to the development of distant metastasis. Furthermore, the data suggest that PA involvement is distal to local invasion in the metastatic cascade.
Manni
Andrea
A
Department of Medicine, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey 17033, USA. amanni@psu.edu
Washington
Sharlene
S
Griffith
James W
JW
Verderame
Michael F
MF
Mauger
David
D
Demers
Laurence M
LM
Samant
Rajeev S
RS
Welch
Danny R
DR
D000818:Animals; D015317:Biogenic Polyamines / Q000494:pharmacology*; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000473:pathology*; D003094:Collagen; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007797:Laminin; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008198:Lymph Nodes / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics; D054778:NM23 Nucleoside Diphosphate Kinases; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins; D009701:Nucleoside-Diphosphate Kinase; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011506:Proteins / Q000235:genetics; D011509:Proteoglycans; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D014746:Vimentin / Q000378:metabolism
C410024:BRMS1 protein, human; D015317:Biogenic Polyamines; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D054778:NM23 Nucleoside Diphosphate Kinases; D009363:Neoplasm Proteins; D065108:Ornithine Decarboxylase Inhibitors; D011506:Proteins; D011509:Proteoglycans; D012097:Repressor Proteins; D014157:Transcription Factors; D014746:Vimentin; C059485:matrigel; D003094:Collagen; D009701:Nucleoside-Diphosphate Kinase; D020559:Monomeric GTP-Binding Proteins; D009955:Ornithine Decarboxylase; D000518:Eflornithine