Tiling path genomic profiling of grade 3 invasive ductal breast cancers

Clin Cancer Res. 2009 Apr 15;15(8):2711-22. doi: 10.1158/1078-0432.CCR-08-1878. Epub 2009 Mar 24.


Purpose: To characterize the molecular genetic profiles of grade 3 invasive ductal carcinomas of no special type using high-resolution microarray-based comparative genomic hybridization (aCGH) and to identify recurrent amplicons harboring putative therapeutic targets associated with luminal, HER-2, and basal-like tumor phenotypes.

Experimental design: Ninety-five grade 3 invasive ductal carcinomas of no special type were classified into luminal, HER-2, and basal-like subgroups using a previously validated immunohistochemical panel. Tumor samples were microdissected and subjected to aCGH using a tiling path 32K BAC array platform. Selected regions of recurrent amplification were validated by means of in situ hybridization. Expression of genes pertaining to selected amplicons was investigated using quantitative real-time PCR and gene silencing was done using previously validated short hairpin RNA constructs.

Results: We show that basal-like and HER-2 tumors are characterized by "sawtooth" and "firestorm" genetic patterns, respectively, whereas luminal cancers were more heterogeneous. Apart from confirming known amplifications associated with basal-like (1q21, 10p, and 12p), luminal (8p12, 11q13, and 11q14), and HER-2 (17q12) cancers, we identified previously unreported recurrent amplifications associated with each molecular subgroup: 19q12 in basal-like, 1q32.1 in luminal, and 14q12 in HER-2 cancers. PPM1D gene amplification (17q23.2) was found in 20% and 8% of HER-2 and luminal cancers, respectively. Silencing of PPM1D by short hairpin RNA resulted in selective loss of viability in tumor cell lines harboring the 17q23.2 amplification.

Conclusions: Our results show the power of aCGH analysis in unraveling the genetic profiles of specific subgroups of cancer and for the identification of novel therapeutic targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Carcinoma, Ductal, Breast / genetics*
  • Carcinoma, Ductal, Breast / pathology*
  • Cell Line, Tumor
  • Cyclin D1 / genetics
  • Estrogen Receptor alpha / genetics
  • Gene Amplification / genetics
  • Gene Dosage / genetics
  • Gene Expression Profiling
  • Gene Silencing
  • Genes, erbB-1 / genetics
  • Genes, erbB-2 / genetics
  • Humans
  • Neoplasm Staging
  • Phosphoprotein Phosphatases / genetics
  • Protein Phosphatase 2C


  • CCND1 protein, human
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Cyclin D1
  • PPM1D protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C