title: LMTK3 is implicated in endocrine resistance via multiple signaling pathways.
abstract: Resistance to endocrine therapy in breast cancer is common. With the aim of discovering new molecular targets for breast cancer therapy, we have recently identified LMTK3 as a regulator of the estrogen receptor-alpha (ERα) and wished to understand its role in endocrine resistance. We find that inhibition of LMTK3 in a xenograft tamoxifen (Tam)-resistant (BT474) breast cancer mouse model results in re-sensitization to Tam as demonstrated by a reduction in tumor volume. A whole genome microarray analysis, using a BT474 cell line, reveals genes significantly modulated (positively or negatively) after LMTK3 silencing, including some that are known to be implicated in Tam resistance, notably c-MYC, HSPB8 and SIAH2. We show that LMTK3 is able to increase the levels of HSPB8 at a transcriptional and translational level thereby protecting MCF7 cells from Tam-induced cell death, by reducing autophagy. Finally, high LMTK3 levels at baseline in tumors are predictive for endocrine resistance; therapy does not lead to alteration in levels, whereas in patient's plasma samples, acquired LMTK3 gene amplification (copy number variation) was associated with relapse while receiving Tam. In aggregate, these data support a role for LMTK3 in both innate (intrinsic) and acquired (adaptive) endocrine resistance in breast cancer.
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Stebbing
authors.forename: A
authors.initials: A
authors.lastname: Filipovic
authors.forename: L C
authors.initials: LC
authors.lastname: Lit
authors.forename: K
authors.initials: K
authors.lastname: Blighe
authors.forename: A
authors.initials: A
authors.lastname: Grothey
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: Y
authors.initials: Y
authors.lastname: Miki
authors.forename: L W
authors.initials: LW
authors.lastname: Chow
authors.forename: R C
authors.initials: RC
authors.lastname: Coombes
authors.forename: H
authors.initials: H
authors.lastname: Sasano
authors.forename: J A
authors.initials: JA
authors.lastname: Shaw
authors.forename: G
authors.initials: G
authors.lastname: Giamas
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004703:Endocrine System / Q000187:drug effects* / Q000473:pathology*; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D047428:Protein Kinase Inhibitors; D013629:Tamoxifen; C560359:LMTK3 protein, human; D017346:Protein Serine-Threonine Kinases