High-mobility group A1a protein regulates Ras/ERK signaling in MCF-7 human breast cancer cells

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Abstract
High-mobility group (HMG) A1 proteins are gene regulatory factors whose overexpression is frequently observed in naturally occurring human cancers. The overexpression of transgenic HMGA1 proteins in cells results in neoplastic transformation and promotes progression to malignant cellular phenotypes. To understand the underlying molecular and biological events involved in these phenomena, we used oligonucleotide microarray analyses to generate an HMGA1a-induced expression profile for approximately 22,000 genes. This gene expression profile was generated using a well-characterized transgenic human MCF-7 mammary adenocarcinoma cell line in which overexpression of transgenic HMGA1 promotes a transition to a more malignant and metastatic phenotype. Microarray expression analyses, together with independent quantitative real-time reverse transcriptase polymerase chain reaction results, indicate that HMGA1a regulates genes involved in the Ras-extracellular signal-related kinase (Ras/ERK) mitogenic signaling pathway, including KIT ligand and caveolins 1 and 2. We also found that many cholesterol biosynthesis genes were decreased in cells overexpressing HMGA1a. Cholesterol depletion, decreased caveolin, and increased KIT ligand expression, are all independently associated with the activation of Ras/ERK signaling. Upon further analysis, we found that sensitivity to epidermal growth factor activation of ERK phosphorylation was significantly higher, and that cholesterol was significantly depleted, in cells overexpressing HMGA1a. The cumulative evidence indicates that one likely mechanism by which the HMGA1a protein promotes malignant changes in cells is through increased sensitivity to the activation of the Ras/ERK signaling pathway.