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Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures

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Abstract

Bypassing estrogen receptor (ER) signaling during development of endocrine resistance remains the most common cause of disease progression and mortality in breast cancer patients. To date, the majority of molecular research on ER action in breast cancer has occurred in cell line models derived from late stage disease. Here we describe patient-derived ER+ luminal breast tumor models for the study of intratumoral hormone and receptor action. Human breast tumor samples obtained from patients post surgery were immediately transplanted into NOD/SCID or NOD/SCID/ILIIrg−/− mice under estrogen supplementation. Five transplantable patient-derived ER+ breast cancer xenografts were established, derived from both primary and metastatic cases. These were assessed for estrogen dependency, steroid receptor expression, cancer stem cell content, and endocrine therapy response. Gene expression patterns were determined in select tumors ±estrogen and ±endocrine therapy. Xenografts morphologically resembled the patient tumors of origin, and expressed similar levels of ER (5–99 %), and progesterone and androgen receptors, over multiple passages. Four of the tumor xenografts were estrogen dependent, and tamoxifen or estrogen withdrawal (EWD) treatment abrogated estrogen-dependent growth and/or tumor morphology. Analysis of the ER transcriptome in select tumors revealed notable differences in ER mechanism of action, and downstream activated signaling networks, in addition to identifying a small set of common estrogen-regulated genes. Treatment of a naïve tumor with tamoxifen or EWD showed similar phenotypic responses, but relatively few similarities in estrogen-dependent transcription, and affected signaling pathways. Several core estrogen centric genes were shared with traditional cell line models. However, novel tumor-specific estrogen-regulated potential target genes, such as cancer/testis antigen 45, were uncovered. These results evoke the importance of mapping both conserved and tumor-unique ER programs in breast cancers. Furthermore, they underscore the importance of primary xenografts for improved understanding of ER+ breast cancer heterogeneity and development of personalized therapies.

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Abbreviations

AI:

Aromatase inhibitors

ALDH:

Aldehyde dehydrogenase

AR:

Androgen receptor

AS:

Ascites

CK5:

Cytokeratin 5

CT45:

Cancer/testis antigen 45

ER:

Estrogen receptor

EWD:

Estrogen withdrawal

GEO:

Gene expression omnibus

IHC:

Immunohistochemisty

MPA:

Medroxyprogesterone acetate

PE:

Pleural effusion

PR:

Progesterone receptor

PT:

Primary tumor

qPCR:

Quantitative PCR

TN:

Triple negative

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Acknowledgments

The authors thank Robert Tsay for providing tissue from pathological specimens, Lisa Litzenberger for graphics help, Audrie Van Bokhoven for the AR control slides, Britta Jacobsen and Elizabeth Wellberg for critical review of the manuscript, and the University of Colorado Cancer Center Breast Cancer Tissue Bank, Tissue Procurement, and Flow Cytometry Cores for their excellent services. This work was supported, in part, by grants from the Grohne Cancer Research Fund (P. Kabos), ASCO Young Investigator Award (P. Kabos), the National Institutes of Health R01 CA140985 (C. Sartorius), the Wendy Will Case Foundation (C. Sartorius), the University of Colorado Cancer Center (P. Kabos and C. Sartorius), and the Martha Cannon Dear Professorship (A. Elias).

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The authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, 80045, CO, USA

    Peter Kabos, Chunling Li, Enos Kline & Anthony Elias

  2. Department of Pathology, University of Colorado Denver Anschutz Medical Campus Center, 12801 E 17th Ave MS8104, Aurora, 80045, CO, USA

    Jessica Finlay-Schultz, Joshua Wisell, Christopher A. Manuel, Susan M. Edgerton & Carol A. Sartorius

  3. Department of Surgery, University of Colorado Denver Anschutz Medical Campus, Aurora, 80045, CO, USA

    Christina Finlayson

  4. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, 27599, NC, USA

    J. Chuck Harrell

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  1. Peter Kabos
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Correspondence to Carol A. Sartorius.

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Kabos, P., Finlay-Schultz, J., Li, C. et al. Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures. Breast Cancer Res Treat 135, 415–432 (2012). https://doi.org/10.1007/s10549-012-2164-8

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  • DOI: https://doi.org/10.1007/s10549-012-2164-8

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