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Molecular profiles of progesterone receptor loss in human breast tumors

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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.

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Abbreviations

ER:

Estrogen receptor alpha

PR:

Progesterone receptor

IHC:

Immunohistochemistry

CNA:

Copy number alteration

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Acknowledgements

This work was supported in part by NIH grants P30 CA125123, P50 CA58183, and 5P01 CA30195-25, and the Dan L. Duncan Cancer Center at Baylor College of Medicine.

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Authors and Affiliations

  1. Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, One Baylor Plaza MS 305, BCM 600, Houston, TX, 77030, USA

    Chad J. Creighton, C. Kent Osborne, Susan G. Hilsenbeck, Adrian V. Lee & Rachel Schiff

  2. The Breast Center, Baylor College of Medicine, One Baylor Plaza, BCM 600, Houston, TX, 77030, USA

    C. Kent Osborne, Gary C. Chamness, Susan G. Hilsenbeck, Adrian V. Lee & Rachel Schiff

  3. Department of Medicine, Baylor College of Medicine, One Baylor Plaza, BCM 600, Houston, TX, 77030, USA

    Chad J. Creighton, C. Kent Osborne, Gary C. Chamness, Susan G. Hilsenbeck, Adrian V. Lee & Rachel Schiff

  4. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, BCM 600, Houston, TX, 77030, USA

    C. Kent Osborne, Adrian V. Lee & Rachel Schiff

  5. Division of Diagnostic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Marc J. van de Vijver, Hugo M. Horlings & Dimitry Nuyten

  6. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands

    Marc J. van de Vijver

  7. Department of Medical Oncology, Erasmus MC, Josephine Nefkens Institute, Rotterdam, The Netherlands

    John A. Foekens & Jan G. Klijn

  8. Veridex LLC, A Johnson & Johnson Company, New Jersey, NY, USA

    Yixin Wang & Yi Zhang

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  1. Chad J. Creighton
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Corresponding author

Correspondence to Chad J. Creighton.

Additional information

Adrian V. Lee and Rachel Schiff contributed equally to this work.

Electronic Supplementary Material

Below is the link to the electronic supplementary material. For the Wang, Miller, and van de Vijver datasets, profiles used in the analysis, along with biochemical assay or IHC values. The complete list of genes in the ER+/PR+ and ER−/PR− signatures.

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Creighton, C.J., Kent Osborne, C., van de Vijver, M.J. et al. Molecular profiles of progesterone receptor loss in human breast tumors. Breast Cancer Res Treat 114, 287–299 (2009). https://doi.org/10.1007/s10549-008-0017-2

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