title: Annexin-A1 and caldesmon are associated with resistance to tamoxifen in estrogen receptor positive recurrent breast cancer.
abstract: Tamoxifen therapy resistance constitutes a major cause of death in patients with recurrent estrogen receptor (ER) positive breast cancer. Through high resolution mass spectrometry (MS), we previously generated a 4-protein predictive signature for tamoxifen therapy outcome in recurrent breast cancer. ANXA1 and CALD1, which were not included in the classifier, were however the most differentially expressed proteins. We first evaluated the clinical relevance of these markers in our MS cohort, followed by immunohistochemical (IHC) staining on an independent set of tumors incorporated in a tissue microarray (TMA) and regression analysis in relation to time to progression (TTP), clinical benefit and objective response. In order to assess which mechanisms ANXA1 and CALD1 might been involved in, we performed Ingenuity pathway analysis (IPA) on ANXA1 and CALD1 correlated proteins in our MS cohort. ANXA1 (Hazard ratio [HR] = 1.83; 95% confidence interval [CI]: 1.22-2.75; P = 0.003) and CALD1 (HR = 1.57; 95% CI: 1.04-2.36; P = 0.039) based patient stratification showed significant association to TTP, while IHC staining on TMA showed that both ANXA1 (HR = 1.82; 95% CI: 1.12-3.00; P = 0.016) and CALD1 (HR = 2.29; 95% CI: 1.40-3.75; P = 0.001) expression was associated with shorter TTP independently of traditional predictive factors. Pearson correlation analysis showed that the majority of proteins correlated to ANXA1 also correlated with CALD1. IPA indicated that ANXA1 and CALD1 were associated with ER-downregulation and NFκB signaling. We hereby report that ANXA1 and CALD1 proteins are independent markers for tamoxifen therapy outcome and are associated to fast tumor progression.
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Tommaso
authors.initials: T
authors.lastname: De Marchi
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Timmermans
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Smid
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.affiliation: Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Christoph
authors.initials: C
authors.lastname: Stingl
authors.affiliation: Division of Medical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Opdam
authors.affiliation: Division of Medical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.affiliation: Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.affiliation: Department of Pathology, Maasstad Hospital, Rotterdam, The Netherlands.
authors.forename: Mike
authors.initials: M
authors.lastname: Kliffen
authors.affiliation: Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Carolien H M
authors.initials: CH
authors.lastname: van Deurzen
authors.affiliation: Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Theo M
authors.initials: TM
authors.lastname: Luider
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.|Cancer Genomics Center Netherlands, Amsterdam, The Netherlands.
authors.forename: John W
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Arzu
authors.initials: A
authors.lastname: Umar
mesh_terms: D017305:Annexin A1 / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002148:Calmodulin-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen / Q000627:therapeutic use*; D046888:Tissue Array Analysis; D016896:Treatment Outcome
chemical_list: D017305:Annexin A1; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D002148:Calmodulin-Binding Proteins; D011960:Receptors, Estrogen; D013629:Tamoxifen
keywords: Annexin-A1; caldesmon; clinical proteomics; metastatic breast cancer; tamoxifen resistance