FRA-1 expression level regulates proliferation and invasiveness of breast cancer cells.
Breast cancer progression is likely a multistep process involving the activation and inactivation of a number of genes. Previously, we showed that the mRNA coding for Fra-1, a FOS family member and an AP-1 transcription factor component, was highly expressed in the more invasive estrogen receptor negative (ER-) breast cancer cell lines. We used a tet-off system to stably overexpress Fra-1 in MCF7 ER+ cells and evaluate the impact of Fra-1 on this aggressive phenotype. Conversely, Fra-1 was silenced in highly invasive ER-MDA-MB231 cells using RNA interference. We report that in both systems the Fra-1 expression level was positively associated with cell proliferation, cell motility and invasiveness assessed in vitro. In addition, Fra-1 inhibition in fibroblastoid ER- cells, which formed colonies with large stellate projections in Matrigel, resulted in morphological changes. Cells acquired an epithelioid shape and had a spherical appearance in Matrigel. Fra-1 regulated several genes, implicated in invasion, angiogenesis and cell proliferation independently of beta1-integrin activation, and directly induced MMP-1 and MMP-9 promoter activity. These overall results show that high Fra-1 expression is associated with a more malignant cell phenotype and suggest that Fra-1 could have a pivotal role in breast cancer progression.
Belguise
Karine
K
Inserm U540, Endocrinologie Moléculaire et Cellulaire des Cancers, 60 Rue de Navacelles, 34090 Montpellier, France.
Kersual
Nathalie
N
Galtier
Florence
F
Chalbos
Dany
D
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D004338:Drug Combinations; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology; D007797:Laminin / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D009361:Neoplasm Invasiveness / Q000235:genetics; D011509:Proteoglycans / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D018808:Transcription Factor AP-1 / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D000099169:Fos-Related Antigen 1
D003094:Collagen; D004318:Doxycycline; D004338:Drug Combinations; D019012:Integrin beta1; D007797:Laminin; D020781:Matrix Metalloproteinase 1; D020780:Matrix Metalloproteinase 9; D011509:Proteoglycans; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D019715:Tissue Inhibitor of Metalloproteinase-1; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D000099169:Fos-Related Antigen 1; C059485:matrigel