title: Expression of transmembrane protein 26 (TMEM26) in breast cancer and its association with drug response.
abstract: We have previously shown that stromal cells desensitize breast cancer cells to the anti-estrogen fulvestrant and, along with it, downregulate the expression of TMEM26 (transmembrane protein 26). In an effort to study the function and regulation of TMEM26 in breast cancer cells, we found that breast cancer cells express non-glycosylated and N-glycosylated isoforms of the TMEM26 protein and demonstrate that N-glycosylation is important for its retention at the plasma membrane. Fulvestrant induced significant changes in expression and in the N-glycosylation status of TMEM26. In primary breast cancer, TMEM26 protein expression was higher in ERα (estrogen receptor α)/PR (progesterone receptor)-positive cancers. These data suggest that ERα is a major regulator of TMEM26. Significant changes in TMEM26 expression and N-glycosylation were also found, when MCF-7 and T47D cells acquired fulvestrant resistance. Furthermore, patients who received aromatase inhibitor treatment tend to have a higher risk of recurrence when tumoral TMEM26 protein expression is low. In addition, TMEM26 negatively regulates the expression of integrin β1, an important factor involved in endocrine resistance. Data obtained by spheroid formation assays confirmed that TMEM26 and integrin β1 can have opposite effects in breast cancer cells. These data are consistent with the hypothesis that, in ERα-positive breast cancer, TMEM26 may function as a tumor suppressor by impeding the acquisition of endocrine resistance. In contrast, in ERα-negative breast cancer, particularly triple-negative cancer, high TMEM26 expression was found to be associated with a higher risk of recurrence. This implies that TMEM26 has different functions in ERα-positive and -negative breast cancer.
authors.affiliation: Otto-von-Guericke-Universität Magdeburg, Institut für Pathologie, Magdeburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Nass
authors.affiliation: Klinik für Gynäkologie, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Dittmer
authors.affiliation: Klinik für Gynäkologie, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Vicky
authors.initials: V
authors.lastname: Hellwig
authors.affiliation: Klinik für Gynäkologie, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Theresia
authors.initials: T
authors.lastname: Lange
authors.affiliation: Klinik für Gynäkologie, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Johanna Mirjam
authors.initials: JM
authors.lastname: Beyer
authors.affiliation: Klinik für Gynäkologie, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Leyh
authors.affiliation: Otto-von-Guericke-Universität Magdeburg, Universitätsfrauenklinik, Magdeburg, Germany.
authors.forename: Atanas
authors.initials: A
authors.lastname: Ignatov
authors.affiliation: Otto-von-Guericke-Universität Magdeburg, Universitätsfrauenklinik, Magdeburg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Weiβenborn
authors.affiliation: Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, Copenhagen, Denmark.|Present address: Department of Surgery, Koege Hospital, Koege, Denmark.
authors.forename: Tove
authors.initials: T
authors.lastname: Kirkegaard
authors.affiliation: Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Lykkesfeldt
authors.affiliation: Otto-von-Guericke-Universität Magdeburg, Institut für Pathologie, Magdeburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kalinski
authors.affiliation: Klinik für Gynäkologie, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Dittmer
mesh_terms: D054316:Biomarkers, Pharmacological / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000235:genetics / Q000378:metabolism
chemical_list: D054316:Biomarkers, Pharmacological; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D019012:Integrin beta1; D008565:Membrane Proteins; C578535:TMEM26 protein, human; D000077267:Fulvestrant; D004958:Estradiol; D012313:RNA
keywords: anti-estrogen resistance; estrogen receptor; integrin beta1; sonic hedgehog; triple-negative breast cancer