Retinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer

• Published in: Nature communications 2013, Vol.4 (1), p.2175-2175, Article 2175
• Main Authors: Johansson, Henrik J., Sanchez, Betzabe C., Mundt, Filip, Forshed, Jenny, Kovacs, Aniko, Panizza, Elena, Hultin-Rosenberg, Lina, Lundgren, Bo, Martens, Ulf, Máthé, Gyöngyvér, Yakhini, Zohar, Helou, Khalil, Krawiec, Kamilla, Kanter, Lena, Hjerpe, Anders, Stål, Olle, Linderholm, Barbro K., Lehtiö, Janne
• Format: Article
• Language: English
• Subjects: 631/45/475; 631/67/1059/2326; 631/67/1347; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal - therapeutic use; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Cancer and Oncology; Cancer och onkologi; Cell Line, Tumor; Chemotherapy, Adjuvant; Drug Resistance, Neoplasm - genetics; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; Mass spectrometry; MEDICIN; MEDICINE; Middle Aged; multidisciplinary; Neoplasm Recurrence, Local; Organ Specificity; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; Retinoic Acid Receptor alpha; Science; Science (multidisciplinary); Survival Analysis; Tamoxifen - therapeutic use
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3175

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. Many patients with breast cancer develop resistance to the drug tamoxifen and relapse. Here Johansson et al . identify the nuclear receptor retinoic acid receptor alpha (RARA) as a marker of tamoxifen resistance and show that RARA expression correlates negatively with relapse-free survival of patients.