Molecular signatures of neoadjuvant endocrine therapy for breast cancer: characteristics of response or intrinsic resistance

  • Djuana M. E. Harvell
  • Nicole S. Spoelstra
  • Meenakshi Singh
  • James L. McManaman
  • Christina Finlayson
  • Tzu Phang
  • Susan Trapp
  • Lawrence Hunter
  • Wendy W. Dye
  • Virginia F. Borges
  • Anthony Elias
  • Kathryn B. Horwitz
  • Jennifer K. Richer
Preclinical Study

Abstract

Approximately 30% of patients with estrogen receptor (ER) positive breast cancers exhibit de novo or intrinsic resistance to endocrine therapies. The purpose of this study was to define genes that distinguish ER+ resistant from ER+ responsive tumors, prior to the start of hormone therapies. Previously untreated post-menopausal patients with ER+ breast cancers were treated for 4 months in a neoadjuvant setting with the aromatase inhibitor exemestane alone, or in combination with the antiestrogen tamoxifen. Matched pre- and post-treatment tumor samples from the same patient, were analyzed by gene expression profiling and were correlated with response to treatment. Genes associated with tumor shrinkage achieved by estrogen blockade therapy were identified, as were genes associated with resistance to treatment. Prediction Analysis of Microarrays (PAM) identified 50 genes that can predict response or intrinsic resistance to neoadjuvant endocrine therapy of ER+ tumors, 8 of which have been previously implicated as useful biomarkers in breast cancer. In summary, we identify genes associated with response to endocrine therapy that may distinguish ER+, hormone responsive breast cancers, from ER+ tumors that exhibit intrinsic or de novo resistance. We suggest that the estrogen signaling pathway is aberrant in ER+ tumors with intrinsic resistance. Lastly, the studies show upregulation of a “lipogenic pathway” in non-responsive ER+ tumors that may serve as a marker of intrinsic resistance. This pathway may represent an alternative target for therapeutic intervention.

Keywords

Breast cancer Neoadjuvant endocrine therapy Estrogen receptors Androgen receptors Expression profiling Aromatase inhibitors Tamoxifen Lipogenic phenotype 

Abbreviations

ER

Estrogen receptors

PR

Progesterone receptors

AI

Aromatase inhibitors

R

Responders

NR

Non-responders

PLIN

Perilipin

Supplementary material

10549_2008_9897_MOESM1_ESM.xls (243 kb)
(XLS 243 kb)
10549_2008_9897_MOESM2_ESM.ppt (946 kb)
(PPT 946 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Djuana M. E. Harvell
    • 1
  • Nicole S. Spoelstra
    • 1
  • Meenakshi Singh
    • 2
  • James L. McManaman
    • 3
  • Christina Finlayson
    • 4
  • Tzu Phang
    • 5
  • Susan Trapp
    • 6
  • Lawrence Hunter
    • 6
  • Wendy W. Dye
    • 1
  • Virginia F. Borges
    • 7
  • Anthony Elias
    • 7
  • Kathryn B. Horwitz
    • 1
    • 2
  • Jennifer K. Richer
    • 1
    • 2
  1. 1.Department of Medicine, Division of Endocrinology, Metabolism and DiabetesUniversity of Colorado Health Sciences CenterAuroraUSA
  2. 2.Department of PathologyUniversity of Colorado Health Sciences CenterAuroraUSA
  3. 3.Department of Obstetrics and GynecologyUniversity of Colorado Health Sciences CenterAuroraUSA
  4. 4.Department of SurgeryUniversity of Colorado Health Sciences CenterAuroraUSA
  5. 5.Department of Medicine, Division of Pulmonary Sciences and Critical Care MedicineUniversity of Colorado Health Sciences CenterAuroraUSA
  6. 6.Computational Bioscience ProgramUniversity of Colorado Health Sciences CenterAuroraUSA
  7. 7.Department of Medicine, Division of Medical OncologyUniversity of Colorado Health Sciences CenterAuroraUSA

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