title: Estrogen receptor-α variant, ER-α36, is involved in tamoxifen resistance and estrogen hypersensitivity.
abstract: Antiestrogens such as tamoxifen (TAM) provided a successful treatment for estrogen receptor (ER)-positive breast cancer for the past four decades. However, most breast tumors are eventually resistant to TAM therapy. The molecular mechanisms underlying TAM resistance have not been well established. Recently, we reported that breast cancer patients with tumors expressing high concentrations of ER-α36, a variant of ER-α, benefited less from TAM therapy than those with low concentrations of ER-α36, suggesting that increased ER-α36 concentration is one of the underlying mechanisms of TAM resistance. Here, we investigated the function and underlying mechanism of ER-α36 in TAM resistance. We found that TAM increased ER-α36 concentrations, and TAM-resistant MCF7 cells expressed high concentrations of ER-α36. In addition, MCF7 cells with forced expression of recombinant ER-α36 and H3396 cells expressing high concentrations of endogenous ER-α36 were resistant to TAM. ER-α36 down-regulation in TAM-resistant cells with the short hairpinRNA method restored TAM sensitivity. We also found that TAM acted as a potent agonist by activating phosphorylation of the AKT kinase in ER-α36-expressing cells. Finally, we found that cells with high concentration of ER-α36 protein were hypersensitive to estrogen, activating ERK phosphorylation at picomolar range. Our results thus demonstrated that elevated ER-α36 concentration is one of the mechanisms by which ER-positive breast cancer cells escape TAM therapy and provided a rational to develop novel therapeutic approaches for TAM-resistant patients by targeting ER-α36.
authors.affiliation: Department of Medical Microbiology, Creighton University Medical School, Criss III, Room 352, 2500 California Plaza, Omaha, Nebraska 68178, USA. zywang@creighton.edu
authors.forename: Xiantian
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhao-Yi
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D004967:Estrogens; D020033:Protein Isoforms; D013629:Tamoxifen; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases