title: Adaptive hypersensitivity to estrogen: mechanism for sequential responses to hormonal therapy in breast cancer.
abstract: Clinical observations demonstrate that women with breast cancer often respond to subsequent endocrine manipulation after resistance to initial hormonal therapy develops. As a mechanistic explanation for these findings, we hypothesized that human breast tumors can adapt in response to the pressure exerted by endocrine therapy with development of hypersensitivity to estradiol. To understand the signaling pathways responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term deprivation of estradiol (LTED) causes adaptive hypersensitivity. Even though the estrogen receptor alpha (ERalpha) is markedly up-regulated in LTED cells, the enhanced responses to estradiol do not appear to involve mechanisms acting at the level of transcription of estrogen-regulated genes. We found that ERalpha co-opts a classical growth factor pathway and induces rapid nongenomic effects that are enhanced in LTED cells. Estradiol binds to cell membrane-associated ERs, physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb2 and Sos, which result in the rapid activation of mitogen-activated protein kinase. These nongenomic effects of estradiol produced biological effects, as evidenced by Elk-1 activation and by morphological changes in cell membranes. The mechanistic pathways involved in adaptive hypersensitivity suggest that inhibitors of the mitogen-activated protein kinase and phosphatidylinositol-3-OH kinase pathways might prevent the development of adaptive hypersensitivity and allow more prolonged efficacy of endocrine therapies.
authors.affiliation: Department of Medicine, University of Virginia Health Sciences System, 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: Zhenguo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Yue
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D002455:Cell Division; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005260:Female; D051380:GRB2 Adaptor Protein; D006728:Hormones / Q000627:therapeutic use*; D006801:Humans; D020935:MAP Kinase Signaling System; D018613:Microscopy, Confocal; D009376:Neoplasms, Hormone-Dependent / Q000628:therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D020839:Son of Sevenless Protein, Drosophila / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047628:Estrogen Receptor alpha; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D006728:Hormones; D011506:Proteins; D011960:Receptors, Estrogen; D020839:Son of Sevenless Protein, Drosophila; D004958:Estradiol; D019869:Phosphatidylinositol 3-Kinases