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Adaptation to Estradiol Deprivation Causes Up-Regulation of Growth Factor Pathways and Hypersensitivity to Estradiol in Breast Cancer Cells

  • Richard J. Santen
  • Robert X. Song
  • Shigeru Masamura
  • Wei Yue
  • Ping Fan
  • Tetsuya Sogon
  • Shin-ichi Hayashi
  • Kei Nakachi
  • Hidtek Eguchi
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 630)

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 adapts and develop hypersensitivity to estradiol. Several mechanisms are associated with this response including up-regulation of ERα and the MAP kinase, PI-3-kinase and mTOR growth factor pathways. ERα 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 membrance-associated ERα 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 of estradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membrances. Additional effects include activation of the PI-3-kinase and mTOR pathways through estradiol-induced binding of ERα to the IGF-1 and EGF receptors.

A major question is how ERα locates in the plasma membrance since it does not contain an inherent membrance localization signal. We have provided evidence that the IGF-1 receptor serves as an anchor for ERα in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, SHC and the IGF-1 receptor itself. SHC, after binding to ERα, serves as the “glue” which tethers ERα 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 ERα 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 membrance 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 of aromatase 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.

Keywords

Aromatase Inhibitor Growth Factor Pathway Focal Adhesion Point Potent Aromatase Inhibitor Farnesylthiosalicylic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  • Richard J. Santen
    • 1
  • Robert X. Song
    • 1
  • Shigeru Masamura
    • 2
  • Wei Yue
    • 1
  • Ping Fan
    • 1
  • Tetsuya Sogon
    • 3
    • 4
  • Shin-ichi Hayashi
    • 5
  • Kei Nakachi
    • 3
    • 4
  • Hidtek Eguchi
    • 3
    • 4
  1. 1.Division of Endocrinology and MetabolismUniversity of Virginia Health Sciences CenterCharlottesvilleUSA
  2. 2.Department of Surgery Tokyo Dental CollegeIchikawa General HospitalSugano, IchikawaJapan
  3. 3.Department of Molecular EpidemiologyHiroshima University Graduate School of Biomedical SciencesHiroshimaJapan
  4. 4.Department of Radiobiology and Molecular EpidemiologyRadiation Effects Research FoundationHiroshimaJapan
  5. 5.Department of Medical TechnologyTohoku University School of MedicineHiroshimaJapan

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