MTDH Activation by 8q22 Genomic Gain Promotes Chemoresistance and Metastasis of Poor-Prognosis Breast Cancer

Cancer Cell. 2009 Jan 6;15(1):9-20. doi: 10.1016/j.ccr.2008.11.013.

Abstract

Targeted therapy for metastatic diseases relies on the identification of functionally important metastasis genes from a large number of random genetic alterations. Here we use a computational algorithm to map minimal recurrent genomic alterations associated with poor-prognosis breast cancer. 8q22 genomic gain was identified by this approach and validated in an extensive collection of breast tumor samples. Regional gain of 8q22 elevates expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers and is associated with poor clinical outcomes. Functional characterization of MTDH revealed its dual role in promoting metastatic seeding and enhancing chemoresistance. These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aldehyde Dehydrogenase / genetics
  • Aldehyde Dehydrogenase / metabolism
  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cell Line, Tumor
  • Chromosomes, Human, Pair 8 / genetics*
  • Drug Resistance, Neoplasm*
  • Gene Expression Profiling
  • Genome, Human / genetics*
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / pathology
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology
  • Prognosis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-met
  • Receptors, Growth Factor / genetics
  • Receptors, Growth Factor / metabolism
  • Survival Rate
  • Xenograft Model Antitumor Assays

Substances

  • Cell Adhesion Molecules
  • MTDH protein, human
  • Proto-Oncogene Proteins
  • Receptors, Growth Factor
  • ALDH3A1 protein, human
  • Aldehyde Dehydrogenase
  • MET protein, human
  • Proto-Oncogene Proteins c-met

Associated data

  • GEO/GSE9187