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Chapter category: Endocrine

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

Chapter authors:
Richard J. Santen, Robert X. Song, Shigeru Masamura, Wei Yue, Ping Fan, Tetsuya Sogon, Shin-ichi Hayashi, Kei Nakachi and Hidtek Eguchi

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 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 membrane‑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 membranes. 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.rnA major question is how ERα 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 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 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 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.

Richard J. Santen
University of Virginia
Charlottesville, Virginia, U.S.A.

Robert X. Song
Division of Endocrinology and Metabolism, University of Virginia Health Sciences Center

Shigeru Masamura
Department of Surgery, Tokyo Dental College, Ichikawa General Hospital

Wei Yue
Division of Endocrinology and Metabolism, University of Virginia Health Sciences Center

Ping Fan
Division of Endocrinology and Metabolism, University of Virginia Health Sciences Center

Tetsuya Sogon
Department of Molecular Epidemiology, Hiroshima University Graduate School of Biomedical Sciences; Department of Radiobiology and Molecular Research Foundation

Shin-ichi Hayashi
Department of Medical Technology, Tohoku University School of Medicine

Kei Nakachi
Department of Molecular Epidemiology, Hiroshima University Graduate School of Biomedical Sciences; Department of Radiobiology and Molecular Epidemiology, Rediation Effects Research Foundation

Hidtek Eguchi
Department of Molecular Epidemiology, Hiroshima University Graduate School of Biomedical Sciences; Department of Radiobiology and Molecular Epidemiology, Rediation Effects Research Foundation

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