Breast Cancer Research and Treatment

, Volume 135, Issue 2, pp 415–432 | Cite as

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

  • Peter Kabos
  • Jessica Finlay-Schultz
  • Chunling Li
  • Enos Kline
  • Christina Finlayson
  • Joshua Wisell
  • Christopher A. Manuel
  • Susan M. Edgerton
  • J. Chuck Harrell
  • Anthony Elias
  • Carol A. Sartorius
Preclinical Study

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.

Keywords

Breast cancer Estrogen receptors Progesterone receptors Xenografts Tamoxifen Gene regulation Cancer/testis antigens 

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

Supplementary material

10549_2012_2164_MOESM1_ESM.pdf (1.5 mb)
Supplementary material 1 (PDF 1570 kb)
10549_2012_2164_MOESM2_ESM.pdf (111 kb)
Supplementary material 2 (PDF 110 kb)
10549_2012_2164_MOESM3_ESM.pdf (63 kb)
Supplementary material 3 (PDF 62 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Peter Kabos
    • 1
  • Jessica Finlay-Schultz
    • 2
  • Chunling Li
    • 1
  • Enos Kline
    • 1
  • Christina Finlayson
    • 3
  • Joshua Wisell
    • 2
  • Christopher A. Manuel
    • 2
  • Susan M. Edgerton
    • 2
  • J. Chuck Harrell
    • 4
  • Anthony Elias
    • 1
  • Carol A. Sartorius
    • 2
  1. 1.Department of Medicine, Division of Medical OncologyUniversity of Colorado Denver Anschutz Medical CampusAuroraUSA
  2. 2.Department of PathologyUniversity of Colorado Denver Anschutz Medical Campus CenterAuroraUSA
  3. 3.Department of SurgeryUniversity of Colorado Denver Anschutz Medical CampusAuroraUSA
  4. 4.Lineberger Comprehensive Cancer CenterUniversity of North CarolinaChapel HillUSA

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