title: Human epidermal growth factor receptor 2 status modulates subcellular localization of and interaction with estrogen receptor alpha in breast cancer cells.
abstract: OBJECTIVE
  Approximately two-thirds of breast cancer patients respond to endocrine therapy, and this population of patients is estrogen receptor (ER) positive. However, a significant proportion of patients do not respond to hormone therapy. ER hormone responsiveness is widely believed to be influenced by enhanced cross-talk of ER with overexpressed human epidermal growth factor receptor 2 (HER2), and a subgroup of ER-positive tumors coexpress high HER2.
  
  
  METHODS
  Breast cancer cells with or without HER2 overexpression were analyzed for ER status, subcellular localization, and interactions with HER2 signaling components by biochemical and immunological methods. Experiments explored the regulatory interactions between the HER2 and ER pathways and the sensitivity of breast cancer cells to tamoxifen.
  
  
  RESULTS
  Stable or transient or natural HER2 overexpression in ER-positive breast cancer cells promoted the nucleus-to-cytoplasm relocalization of ER, enhanced interactions of ER with HER2, inhibited ER transactivation function, and induced resistance to tamoxifen-mediated growth inhibition of breast cancer cells. In addition, HER2 up-regulation resulted in ER interaction with Sos, a component of Ras signaling, and hyperstimulation of the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2). Conversely, down-regulation of HER2 by the anti-HER2 monoclonal antibody Herceptin led to suppression of ERK1/2 stimulation, restoration of ER to the nucleus, and potentiation of the growth-inhibitory action of tamoxifen.
  
  
  CONCLUSIONS
  The results presented here show for the first time that ER redistribution to the cytoplasm and its interaction with HER2 are important downstream effects of HER2 overexpression, that ERK1/2 is important for ER cytoplasmic localization, and that subcellular localization of ER may play a mechanistic role in determining the responsiveness of breast cancer cells to tamoxifen.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Yang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Barnes
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D015533:Transcriptional Activation; D014162:Transfection; D000068878:Trastuzumab; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D066246:ErbB Receptors; D047628:Estrogen Receptor alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000068878:Trastuzumab; D018631:ras Proteins; C016601:afimoxifene