title: Elevated 80K-H protein in breast cancer: a role for FGF-1 stimulation of 80K-H.
abstract: An increase in fibroblast growth factor-1 (FGF-1) is established as part of the cause of several important cancers including breast cancer, but the mechanisms by which it induces malignant behavior are not known. We now report that the protein 80K-H, a substrate for PKC, appears to be part of this mechanism and that it is increased in breast cancer and localizes to the nucleus as part of the mechanism. Our conclusion is based on an examination of a total of 58 biopsy specimens from human breast cancer patients for the presence of relationships between the 80K-H protein and the following: fibroblast growth factor receptor-1 (FGFR-1), tumor grade, microvessel counts (MVC), estrogen receptor (ER) and progesterone receptor (PgR) status. Based on histological grading and immunohistochemical (IHC) assays, we found strong direct relationships between 80K-H and FGFR-1 (r = 0.49, p = 0.003) and tumor grade (r = 0.42, p = 0.006). A trend for a direct relationship was observed with PgR (r=0.27, p=0.087). Notably, 80K-H immunostaining was largely limited to the epithelial cells of the mammary ducts. Subsequently, we studied the effects of FGF-1 on 80K-H in cultured human mammary carcinoma epithelial cells in order to establish a more direct relationship between these two molecules. We observed that FGF-1 treatment of MCF-7 cells stimulated translocation of 80K-H protein to the cell nucleus, as demonstrated by subcellular fractionation studies. Maximal intranuclear 80K-H was observed approximately 30 minutes following FGF-1 treatment. In addition, FGF-1 treatment of MCF-7 cells increased growth and invasion of MCF-7 cells, as demonstrated by cell proliferation and a modified Boyden chamber assay, respectively. Further support for 80K-H nuclearization was provided by the immunostaining of human breast cancer specimens and computer-assisted identification of a putative nuclear localization signal (NLS) near the amino terminus of 80K-H protein structure. These data support the existence of a previously unrecognized FGF-1/80K-H nuclear pathway in progression of human breast cancer and suggest that 80K-H may be useful for the assessment of breast tumor progression.
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University, HSC, College Station, Texas 77843, USA. forough@tamu.edu
authors.forename: R
authors.initials: R
authors.lastname: Forough
authors.forename: L
authors.initials: L
authors.lastname: Lindner
authors.forename: C
authors.initials: C
authors.lastname: Partridge
authors.forename: B
authors.initials: B
authors.lastname: Jones
authors.forename: G
authors.initials: G
authors.lastname: Guy
authors.forename: G
authors.initials: G
authors.lastname: Clark
mesh_terms: D021581:Active Transport, Cell Nucleus; D001943:Breast Neoplasms / Q000737:chemistry* / Q000473:pathology; D002135:Calcium-Binding Proteins; D002455:Cell Division; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D005959:Glucosidases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010750:Phosphoproteins / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D016220:Fibroblast Growth Factor 1; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005959:Glucosidases; C070368:PRKCSH protein, human