YB-1 alters MT1-MMP trafficking and stimulates MCF-7 breast tumor invasion and metastasis.
YB-1 is a member of the cold shock domain family, with complex roles in DNA structure, gene transcription and translation. YB-1 promotes chromosomal instability, and mammary gland transgenic expression induces tumors with 100% penetrance. YB-1 is linked to poor prognosis in breast carcinoma and is a strong predictor of relapse and disease-specific survival. Survival is directly tied to the extent of local invasion and distal metastasis, processes dependent upon the activity of the membrane type I-matrix metalloproteinase, MT1-MMP. Non-invasive MCF-7 breast adenocarcinoma cells were transfected with YB-1/EGFP. YB-1 protein was detected in the invadopodia of cells with a migratory phenotype. There was increased expression of MT1-MMP protein concentrated at the leading edges of motile cells, which were highly invasive in collagen three-dimensional culture. The rates of MT1-MMP protein endocytosis and recycling to the cell surface were elevated in clones expressing higher levels of YB-1 protein. Control MCF-7 cells formed nonfatal, non-invasive, differentiated adenocarcinomas in vivo. MCF-7 cells expressing a twofold increase in YB-1 formed highly anaplastic tumors with local invasion, pulmonary metastases and high lethality. We conclude that YB-1 contributes to the development of an invasive, metastatic breast carcinoma phenotype by enhanced presentation of MT1-MMP at the sites of cellular invasion.
Lovett
David H
DH
The Department of Medicine, San Francisco Department of Veterans Affairs Medical Center, University of California, The Northern California Institute for Research and Education, San Francisco, CA 94121, USA. david.lovett@va.gov
Cheng
Sunfa
S
Cape
Leslie
L
Pollock
Allan S
AS
Mertens
Peter R
PR
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D051840:Y-Box-Binding Protein 1
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14