title: Retinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer.
abstract: About one-third of oestrogen receptor alpha-positive breast cancer patients treated with tamoxifen relapse. Here we identify the nuclear receptor retinoic acid receptor alpha as a marker of tamoxifen resistance. Using quantitative mass spectrometry-based proteomics, we show that retinoic acid receptor alpha protein networks and levels differ in a tamoxifen-sensitive (MCF7) and a tamoxifen-resistant (LCC2) cell line. High intratumoural retinoic acid receptor alpha protein levels also correlate with reduced relapse-free survival in oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen solely. A similar retinoic acid receptor alpha expression pattern is seen in a comparable independent patient cohort. An oestrogen receptor alpha and retinoic acid receptor alpha ligand screening reveals that tamoxifen-resistant LCC2 cells have increased sensitivity to retinoic acid receptor alpha ligands and are less sensitive to oestrogen receptor alpha ligands compared with MCF7 cells. Our data indicate that retinoic acid receptor alpha may be a novel therapeutic target and a predictive factor for oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen.
authors.affiliation: Department of Oncology/Pathology, Cancer Proteomics Mass Spectrometry, SciLifeLab Stockholm, Karolinska Institute, Stockholm SE-171 21, Sweden.
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Johansson
authors.forename: Betzabe C
authors.initials: BC
authors.lastname: Sanchez
authors.forename: Filip
authors.initials: F
authors.lastname: Mundt
authors.forename: Jenny
authors.initials: J
authors.lastname: Forshed
authors.forename: Aniko
authors.initials: A
authors.lastname: Kovacs
authors.forename: Elena
authors.initials: E
authors.lastname: Panizza
authors.forename: Lina
authors.initials: L
authors.lastname: Hultin-Rosenberg
authors.forename: Bo
authors.initials: B
authors.lastname: Lundgren
authors.forename: Ulf
authors.initials: U
authors.lastname: Martens
authors.forename: Gyöngyvér
authors.initials: G
authors.lastname: Máthé
authors.forename: Zohar
authors.initials: Z
authors.lastname: Yakhini
authors.forename: Khalil
authors.initials: K
authors.lastname: Helou
authors.forename: Kamilla
authors.initials: K
authors.lastname: Krawiec
authors.forename: Lena
authors.initials: L
authors.lastname: Kanter
authors.forename: Anders
authors.initials: A
authors.lastname: Hjerpe
authors.forename: Olle
authors.initials: O
authors.lastname: Stål
authors.forename: Barbro K
authors.initials: BK
authors.lastname: Linderholm
authors.forename: Janne
authors.initials: J
authors.lastname: Lehtiö
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009928:Organ Specificity; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D013629:Tamoxifen