title: Adaptation to estradiol deprivation causes up-regulation of growth factor pathways and hypersensitivity to estradiol in breast cancer cells.
abstract: Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby Long Term Estradiol Deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response including up-regulation of ERalpha and the MAP kinase, PI-3-kinase and mTOR growth factor pathways. ERalpha is 4-10 fold up-regulated as a result of demethylation of its C promoter, This nuclear receptor then co-opts a classical growth factor pathway using SHC, Grb-2 and Sos. This induces rapid nongenomic effects which are enhanced in LTED cells. The molecules involved in the nongenomic signaling process have been identified. Estradiol binds to cell membrane-associated ERalpha which physically associates with the adaptor protein SHC and induces its phosphorylation. In turn, SHC binds Grb-2 and Sos which results in the rapid activation of MAP kinase. These nongenomic effects ofestradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI-3-kinase and mTOR pathways through estradiol-induced binding of ERalpha to the IGF-1 and EGF receptors. A major question is how ERalpha locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-1 receptor serves as an anchor for ERalpha in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, SHC and the IGF-1 receptor itself. SHC, after binding to ERalpha, serves as the "glue" which tethers ERalpha to SHC binding sites on the activated IFG-1 receptors. Use of siRNA methodology to knock down SHC allows the conclusion that SHC is needed for ERalpha to localize in the plasma membrane. In order to abrogate growth factor induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1 and reduces the activation of MAP kinase. We have shown that this drug is a potent inhibitor of mTOR and this provides the major means for inhibition of cell proliferation. The concept of "adaptive hypersensitivity" and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy ofaromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.
authors.affiliation: Division of Endocrinology and Metabolism, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA. rjs5y@virginia.edu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Santen
authors.forename: Robert X
authors.initials: RX
authors.lastname: Song
authors.forename: Shigeru
authors.initials: S
authors.lastname: Masamura
authors.forename: Wei
authors.initials: W
authors.lastname: Yue
authors.forename: Ping
authors.initials: P
authors.lastname: Fan
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Sogon
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Hayashi
authors.forename: Kei
authors.initials: K
authors.lastname: Nakachi
authors.forename: Hidtek
authors.initials: H
authors.lastname: Eguchi
mesh_terms: D000220:Adaptation, Biological / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D004958:Estradiol / Q000172:deficiency* / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008954:Models, Biological; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D004958:Estradiol