HMG-I(Y) recognizes base-unpairing regions of matrix attachment sequences and its increased expression is directly linked to metastatic breast cancer phenotype

• Published in: Cancer research (Chicago, Ill.) Ill.), 1999-11, Vol.59 (22), p.5695-5703
• Main Authors: LIU, W.-M, GUERRA-VLADUSIC, F. K, KURAKATA, S, LUPU, R, KOHWI-SHIGEMATSU, T
• Format: Article
• Language: English
• Subjects: Antisense Elements (Genetics) - administration & dosage; Antisense Elements (Genetics) - genetics; Biological and medical sciences; Blotting, Southern; Blotting, Western; Breast Neoplasms - chemistry; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Estrogens - pharmacology; Female; Gynecology. Andrology. Obstetrics; Heterogeneous-Nuclear Ribonucleoproteins; High Mobility Group Proteins - genetics; High Mobility Group Proteins - isolation & purification; High Mobility Group Proteins - metabolism; HMGA1a Protein; Humans; Mammary gland diseases; Matrix Metalloproteinase Inhibitors; Medical sciences; Molecular Weight; Neoplasm Metastasis; Neoplasm Proteins - genetics; Neoplasm Proteins - isolation & purification; Neoplasm Proteins - metabolism; Neuregulin-1 - genetics; Neuregulin-1 - metabolism; Phenotype; Ribonucleoproteins - genetics; Ribonucleoproteins - metabolism; Transcription Factors - genetics; Transcription Factors - isolation & purification; Transcription Factors - metabolism; Transfection; Tumor Cells, Cultured - drug effects; Tumors
• ISSN: 0008-5472; 1538-7445

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.