title: Heparin-binding epidermal growth factor-like growth factor stimulates androgen-independent prostate tumor growth and antagonizes androgen receptor function.
abstract: Peptide growth factors have been implicated in progression of prostate cancer (PCa) to the androgen-independent state; however, much of the evidence linking diffusible mitogens and survival factors to this process remains circumstantial. Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a prostate stroma-derived factor, promotes survival, proliferation, and neuroendocrine differentiation of androgen-dependent LNCaP PCa cells in vitro. To test whether sustained exposure to HB-EGF can confer an androgen-independent phenotype, we generated stable populations of LNCaP cells that express constitutively a secreted form of HB-EGF (LNCaP/sHB). LNCaP/sHB cells proliferated more rapidly under androgen-depleted conditions in vitro and formed larger tumors with higher frequency in intact and castrated severe combined immunodeficient mice, in comparison to control cells. LNCaP/sHB tumors also expressed higher levels of the neuroendocrine marker, neuron-specific enolase, compared with control tumors. In castrates, increased neuron-specific enolase expression in LNCaP/sHB tumors was associated with reduced androgen receptor (AR) levels. In vitro, AR protein levels were reduced in LNCaP/sHB cells, and in transient transfection assays using an androgen-responsive promoter (mouse mammary tumor virus-long terminal repeat), LNCaP/sHB cells showed reduced sensitivity to dihydrotestosterone compared with controls. This is the first demonstration that continuous exposure of AR-positive PCa cells to a single growth factor can promote an androgen-independent phenotype in vivo. These findings also emphasize the potential role of pathways other than the AR axis in acquisition of androgen independence.
authors.affiliation: The Urologic Laboratory, Department of Urology, Children's Hospital Boston and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Rosalyn M
authors.initials: RM
authors.lastname: Adam
authors.forename: Jayoung
authors.initials: J
authors.lastname: Kim
authors.forename: Jianqing
authors.initials: J
authors.lastname: Lin
authors.forename: Anna
authors.initials: A
authors.lastname: Orsola
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhuang
authors.forename: Dana C
authors.initials: DC
authors.lastname: Rice
authors.forename: Michael R
authors.initials: MR
authors.lastname: Freeman
mesh_terms: D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division; D017077:Culture Media, Conditioned; D013196:Dihydrotestosterone / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D066257:Heparin-binding EGF-like Growth Factor; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010751:Phosphopyruvate Hydratase / Q000032:analysis; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000032:analysis; D012995:Solubility; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D017077:Culture Media, Conditioned; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D004815:Epidermal Growth Factor; D010751:Phosphopyruvate Hydratase