HOXA1-stimulated oncogenicity is mediated by selective upregulation of components of the p44/42 MAP kinase pathway in human mammary carcinoma cells.
Expression of homeobox A1 (HOXA1) results in oncogenic transformation of immortalized human mammary epithelial cells with aggressive tumor formation in vivo. However, the mechanisms by which HOXA1 mediates oncogenic transformation is not well defined. To identify molecules that could potentially be involved in HOXA1-mediated oncogenic transformation, microarray analysis was utilized to characterize and compare the gene expression pattern in response to forced expression or depletion of HOXA1 in human mammary carcinoma cells. Gene expression profiling identified that genes involved in the p44/42 mitogen-activated protein (MAP) kinase activation pathway (GRB2, MAP kinase kinase (MEK1) and SDFR1) or p44/42 MAP kinase-regulated genes (IER3, EPAS1, PCNA and catalase) are downstream expression targets of HOXA1. Forced expression of HOXA1 increased GRB2 and MEK1 mRNA and protein expression and increased p44/42 MAP kinase phosphorylation, activity and Elk-1-mediated transcription. Use of a MEK1 inhibitor demonstrated that increased p44/42 MAP kinase activity is required for the HOXA1-mediated increase in cell proliferation, survival, oncogenicity and oncogenic transformation. Thus, modulation of the p44/42 MAP kinase pathway is one mechanism by which HOXA1 mediates oncogenic transformation of the human mammary epithelial cell.
Mohankumar
K M
KM
The Liggins Institute and National Research Centre for Growth and Development, University of Auckland, Auckland, New Zealand.
Xu
X Q
XQ
Zhu
T
T
Kannan
N
N
Miller
L D
LD
Liu
E T
ET
Gluckman
P D
PD
Sukumar
S
S
Emerald
B S
BS
Lobie
P E
PE
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000502:physiology; D000099261:Homeobox A1 Protein
D018398:Homeodomain Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D000099261:Homeobox A1 Protein