Molecular profiles of progesterone receptor loss in human breast tumors

Breast Cancer Res Treat. 2009 Mar;114(2):287-99. doi: 10.1007/s10549-008-0017-2. Epub 2008 Apr 19.

Abstract

Background: Patient prognosis and response to endocrine therapy in breast cancer correlate with protein expression of both estrogen receptor (ER) and progesterone receptor (PR), with poorer outcome in patients with ER+/PR- compared to ER+/PR+ tumors.

Methods: To better understand the underlying biology of ER+/PR- tumors, we examined RNA expression (n > 1000 tumors) and DNA copy number profiles from five previously published studies of human breast cancers with clinically assigned hormone receptor status (ER+/PR+, ER+/PR-, and ER-/PR-).

Results: We identified an expression "signature" of genes with either elevated or diminished RNA levels specifically in ER+/PR+ compared to ER-/PR- and ER+/PR- tumors. We similarly identified a gene signature specific to ER-/PR- tumors. ER+/PR- tumors, on the other hand, were a mixture of three different subtypes: tumors manifesting the ER+/PR+ signature, tumors manifesting the ER-/PR- signature, and tumors not associating with ER+/PR+ or ER-/PR- tumors (which we considered "true" ER+/PR-). In analyses of both tamoxifen-treated and untreated patients, ER+/PR- breast cancers defined by RNA profiling were associated with poor patient outcome, worse than those with pure ER+/PR+ patterns; these differences were not observed when using clinical assays to assign ER and PR status. ER+/PR- tumors also showed twice as many DNA copy number gains or losses compared to ER+/PR+ and ER-PR- tumors. Targets of transcriptional up-regulation by specific oncogenic pathways, including PI3 K/Akt/mTOR, were enriched in both ER+/PR- and ER-/PR- compared to ER+/PR+ tumors.

Conclusion: ER+/PR- tumors as defined by RNA profiling represent a distinct subset of breast cancer with aggressive features and poor outcome, despite being clinically ER+. Multigene assays derived from our gene signatures could conceivably provide an improved clinical assay for inferring PR status for prognostic and therapeutic purposes.

Publication types

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

MeSH terms

  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Gene Dosage
  • Gene Expression Profiling*
  • Humans
  • Oligonucleotide Array Sequence Analysis
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Prognosis
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Progesterone / genetics*
  • Signal Transduction
  • TOR Serine-Threonine Kinases

Substances

  • Biomarkers, Tumor
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Receptors, Progesterone
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt