LMTK3 is implicated in endocrine resistance via multiple signaling pathways

Oncogene. 2013 Jul 11;32(28):3371-80. doi: 10.1038/onc.2012.343. Epub 2012 Aug 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / drug effects
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic
  • Drug Resistance, Neoplasm* / drug effects
  • Endocrine System / drug effects*
  • Endocrine System / pathology*
  • Female
  • Heat-Shock Proteins / metabolism
  • MCF-7 Cells
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / metabolism*
  • Mice
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction* / drug effects
  • Tamoxifen / pharmacology

Substances

  • HSPB8 protein, human
  • Heat-Shock Proteins
  • Membrane Proteins
  • Protein Kinase Inhibitors
  • Tamoxifen
  • LMTK3 protein, human
  • Protein-Serine-Threonine Kinases