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Sequential changes in gene expression profiles in breast cancers during treatment with the aromatase inhibitor, letrozole

The Pharmacogenomics Journal volume 12, pages 10–21 (2012)Cite this article

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Abstract

The study aim was to identify early (within 14 days) and late changes (by 3 months) in breast cancer gene expression profiles associated with neoadjuvant therapy with letrozole. RNA from sequential tumour biopsies in 54 patients was analyzed on microarrays; changes were determined by frequency, magnitude and significance analyses. Substantially more genes were changed at 3 months (1503) than at 14 days (237). Early changed genes were associated with cell cycle (downregulation), blood vessel development and extracellular matrix (upregulation); late changes included ‘cellular metabolic process’, ‘generation of precursor metabolites and energy’ (decreased) and ‘cell adhesion’ ‘biological adhesion‘ (increased). A striking difference between the early and late changes was the general location of downregulated genes—nuclear structures at 14 days and mitochondria after 3 months. These changes in gene expression profiles provide a new and important database by which to understand molecular mechanisms of letrozole in breast cancers.

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References

  1. Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 2001; 12: 1527–1532.

    Article  CAS  Google Scholar 

  2. Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001; 19: 2596–2606.

    Article  CAS  Google Scholar 

  3. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349: 1793–1802.

    Article  CAS  Google Scholar 

  4. Rose C, Vtoraya O, Pluzanska A, Davidson N, Gershanovich M, Thomas R et al. An open randomised trial of second-line endocrine therapy in advanced breast cancer: comparison of the aromatase inhibitors letrozole and anastrozole. Eur J Cancer 2003; 39: 2318–2327.

    Article  CAS  Google Scholar 

  5. Miller WR . Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer. Semin Oncol 2003; 30 (4 Suppl 14): 3–11.

    Article  CAS  Google Scholar 

  6. Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE . Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol 2002; 20: 751–757.

    Article  CAS  Google Scholar 

  7. Miller WR, Dixon JM . Local endocrine effects of aromatase inhibitors within the breast. J Steroid Biochem Mol Biol 2001; 79: 93–102.

    Article  CAS  Google Scholar 

  8. Miller WR, Larionov AA, Renshaw L, Anderson TJ, White S, Murray J et al. Changes in breast cancer transcriptional profiles after treatment with the aromatase inhibitor, letrozole. Pharmacogenet Genomics 2007; 17: 813–826.

    Article  CAS  Google Scholar 

  9. Miller WR, Larionov A, Renshaw L, Anderson TJ, Walker JR, Krause A et al. Gene expression profiles differentiating between breast cancers clinically responsive or resistant to letrozole. J Clin Oncol 2009; 27: 1382–1387.

    Article  CAS  Google Scholar 

  10. Iqbal S, Anderson TJ, Marson LP, Prescott RJ, Dixon JM, Miller WR . MIB-1 assessments in breast cancers. Breast 2002; 11: 252–256.

    Article  CAS  Google Scholar 

  11. Scherer A, Krause A, Walker JR, Sutton SE, Seron D, Raulf F et al. Optimized protocol for linear RNA amplification and application to gene expression profiling of human renal biopsies. Biotechniques 2003; 34: 546–550, 552–554, 556.

    Article  CAS  Google Scholar 

  12. Kauffmann A, Gentleman R, Huber W . arrayQualityMetrics--a bioconductor package for quality assessment of microarray data. Bioinformatics 2009; 25: 415–416.

    Article  CAS  Google Scholar 

  13. Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 2003; 4: 249–264.

    Article  Google Scholar 

  14. Smyth GK . Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 2004; 3: Article3.

    Article  Google Scholar 

  15. Smyth GK . Limma: Linear models for microarray data. In: Gentleman R, Carey V, Huber W, Irizarry R, Dudoit S (eds). Bioinformatics and Computational Biology Solutions Using R and Bioconductor (Statistics for Biology and Health). Springer: New York, 2005 pp 397–406.

    Google Scholar 

  16. de Hoon MJ, Imoto S, Nolan J, Miyano S . Open source clustering software. Bioinformatics 2004; 20: 1453–1454.

    Article  CAS  Google Scholar 

  17. Saldanha AJ . Java Treeview--extensible visualization of microarray data. Bioinformatics 2004; 20: 3246–3248.

    Article  CAS  Google Scholar 

  18. Zheng Q, Wang XJ . GOEAST: a web-based software toolkit for Gene Ontology enrichment analysis. Nucleic Acids Res 2008; 36 (Web Server issue): W358–W363.

    Article  CAS  Google Scholar 

  19. Miller WR, White S, Dixon JM, Murray J, Renshaw L, Anderson TJ . Proliferation, steroid receptors and clinical/pathological response in breast cancer treated with letrozole. Br J Cancer 2006; 94: 1051–1056.

    Article  CAS  Google Scholar 

  20. Miller WR, Krause A, Larionov A, Evans DB, Anderson TJ, Dixon JM . Genesdiscriminating between Breast Cancers Responsive or Resistant to the aromatase inhibitor, letrozole. Europ J Clin and Med Oncol 2010; 2: 17–22.

    Google Scholar 

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Authors and Affiliations

  1. Edinburgh Breast Unit Research Group, Western General Hospital, Edinburgh, UK

    W R Miller, A Larionov, T J Anderson & J M Dixon

  2. Novartis Institutes for Biomedical Research Basel, Oncology Research, Basel, Switzerland

    D B Evans

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  1. W R Miller
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  2. A Larionov
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  3. T J Anderson
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  4. D B Evans
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  5. J M Dixon
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Correspondence to W R Miller.

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DBE is an employee and share holder of Novartis Pharma AG. Other authors declare no conflict of interest.

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Miller, W., Larionov, A., Anderson, T. et al. Sequential changes in gene expression profiles in breast cancers during treatment with the aromatase inhibitor, letrozole. Pharmacogenomics J 12, 10–21 (2012). https://doi.org/10.1038/tpj.2010.67

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