HMG-I(Y) recognizes base-unpairing regions of matrix attachment sequences and its increased expression is directly linked to metastatic breast cancer phenotype.
Base-unpairing regions (BURs) contain a specialized DNA context with an exceptionally high unwinding propensity, and are typically identified within various matrix attachment regions. A BUR affinity column was used to purify a doublet of Mr 20,000 proteins from human breast carcinoma cells. These proteins were identified as the high-mobility group (HMG) protein, HMG-I, and its splicing variant, HMG-Y. We show that HMG-I(Y) specifically binds BURs. Mutating BURs so as to abrogate their unwinding property greatly reduced their binding affinity to HMG-I(Y). Numerous studies have indicated that elevated HMG-I(Y) expression is correlated with more advanced cancers and with increased metastatic potential. We studied whether the expression of HMG-I(Y) responds to signaling through the heregulin (HRG)-erbB pathway and the extracellular matrix. HMG-I(Y) expression was increased in MCF-7 cells after stable transfection with an HRG expression construct that led cells to acquire estrogen independence and metastasizing ability. A high level of HMG-I(Y) expression was detected in metastatic MDA-MB-231 cells, but the expression was virtually diminished, and the metastasizing ability was lost after cells were stably transfected with an antisense HRG cDNA construct. HMG-I(Y) was also decreased in MDA-MB-231 cells when treated with a chemical inhibitor for matrix metalloproteinase-9 that led to a reduction of invasive capability in vitro. The level of HMG-I(Y) expression, therefore, is dynamically regulated in human breast cancer cells in response to varying types of signaling that affect metastatic ability, including the HRG-erbB pathway and those from the extracellular matrix.
Liu
W M
WM
Lawrence Berkeley National Laboratory, University of California, Berkeley 94720, USA.
Guerra-Vladusic
F K
FK
Kurakata
S
S
Lupu
R
R
Kohwi-Shigematsu
T
T
D016375:Antisense Elements (Genetics) / Q000008:administration & dosage / Q000235:genetics; D015139:Blotting, Southern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D025741:HMGA1a Protein; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006609:High Mobility Group Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D008970:Molecular Weight; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D016375:Antisense Elements (Genetics); D004268:DNA-Binding Proteins; D004967:Estrogens; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006609:High Mobility Group Proteins; D061965:Matrix Metalloproteinase Inhibitors; D009363:Neoplasm Proteins; D020890:Neuregulin-1; D012261:Ribonucleoproteins; D014157:Transcription Factors; D025741:HMGA1a Protein