title: GPER1-mediated IGFBP-1 induction modulates IGF-1-dependent signaling in tamoxifen-treated breast cancer cells.
abstract: Tamoxifen, a selective estrogen receptor modulator, is a commonly prescribed adjuvant therapy for estrogen receptor-α (ERα)-positive breast cancer patients. To determine if extracellular factors contribute to the modulation of IGF-1 signaling after tamoxifen treatment, MCF-7 cells were treated with IGF-1 in conditioned medium (CM) obtained from 4-OHT-treated MCF-7 cells and the accumulation of phospho-Akt (S473) was measured. CM inhibited IGF-1-dependent cell signaling and suggesting the involvement of extracellular factors (ie. IGFBPs). A significant increase in IGFBP-1 mRNA and extracellular IGFBP-1 protein was observed in 4-OHT-treated MCF-7 cells. Knockdown experiments demonstrated that both GPER1 and CREB mediate IGFBP-1 induction. Furthermore, experiments showed that 4-OHT-dependent IGFBP-1 transcription is downstream of GPER1-activation in breast cancer cells. Additionally, neutralization and knockdown experiments demonstrated a role for IGFBP-1 in the observed inhibition of IGF-1 signaling. These results suggested that 4-OHT inhibits IGF-1 signaling via GPER1 and CREB mediated extracellular IGFBP-1 accumulation in breast cancer cells.
authors.affiliation: Molecular Biology Program, New Mexico State University, Las Cruces, NM 88003, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Vaziri-Gohar
authors.affiliation: Molecular Biology Program, New Mexico State University, Las Cruces, NM 88003, USA; Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003, USA. Electronic address: khouston@nmsu.edu.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Houston
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000737:chemistry; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D005260:Female; D006801:Humans; D006915:Hydroxytestosterones / Q000494:pharmacology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: C115163:CREB1 protein, human; D017077:Culture Media, Conditioned; D017362:Cyclic AMP Response Element-Binding Protein; C109584:GPER1 protein, human; D006915:Hydroxytestosterones; C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D013629:Tamoxifen; C032278:4,17 beta-dihydroxy-4-androstene-3-one; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt
keywords: Breast cancer; GPER1; IGF-1; IGFBP-1; Tamoxifen