title: LAMP3 is involved in tamoxifen resistance in breast cancer cells through the modulation of autophagy.
abstract: Lysosome-associated membrane protein 3 (LAMP3) is a member of the LAMP-family of proteins, which are involved in the process of autophagy. Autophagy is induced by tamoxifen in breast cancer cells and may contribute to tamoxifen resistance. In this study, the significance of LAMP3 for tamoxifen resistance in breast cancer was examined. The methods employed included use of clonogenic assays to assess the survival of MCF7 breast cancer cells with LAMP3 knockdown after tamoxifen treatment and of quantitative real-time PCR of LAMP3 to evaluate its predictive value for first-line tamoxifen treatment in patients with advanced breast cancer. Results show that tamoxifen treatment of MCF7 cells induced LAMP3 mRNA expression. LAMP3 knockdown in these cells increased tamoxifen sensitivity. Evaluation of expression of the autophagy markers, LC3B and p62, after LAMP3 knockdown showed increased expression levels, indicating that cells with LAMP3 knockdown have a suppressed ability to complete the autophagic process. In addition, knockdown of autophagy-associated genes resulted in sensitization to tamoxifen. Next, tamoxifen-resistant MCF7 cells were cultured. These cells had a sevenfold higher LAMP3 mRNA expression, showed elevated basal autophagy levels, and could be significantly resensitized to tamoxifen by LAMP3 knockdown. In patients treated with first-line tamoxifen for advanced disease (n=304), high LAMP3 mRNA expression was associated with shorter progression-free survival (P=0.003) and shorter post-relapse overall survival (P=0.040), also in multivariate analysis. Together, these results indicate that LAMP3 contributes to tamoxifen resistance in breast cancer. Tamoxifen-resistant cells are resensitized to tamoxifen by the knockdown of LAMP3. Therefore, LAMP3 may be clinically relevant to countering tamoxifen resistance in breast cancer patients.
authors.affiliation: Departments of Radiation Oncology, Laboratory Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Anika
authors.initials: A
authors.lastname: Nagelkerke
authors.forename: Anieta M
authors.initials: AM
authors.lastname: Sieuwerts
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
mesh_terms: D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D016016:Proportional Hazards Models; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D059666:Lysosomal-Associated Membrane Protein 3
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051907:Lysosomal Membrane Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D013629:Tamoxifen; C114233:LAMP3 protein, human; D059666:Lysosomal-Associated Membrane Protein 3; C502070:MAP1LC3B protein, human
keywords: SERM; breast; estrogen receptor