Functional and genomic characterisation of a xenograft model system for the study of metastasis in triple-negative breast cancer

Cameron N. Johnstone, Andrew D. Pattison, Kylie L. Gorringe, Paul F. Harrison, David R. Powell, Peter Lock, David Baloyan, Matthias Ernst, Alastair G. Stewart, Traude H. Beilharz, Robin L. Anderson

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Triple-negative breast cancer (TNBC) represents 10-20% of all human ductal adenocarcinomas and has a poor prognosis relative to other subtypes. Hence, new molecular targets for therapeutic intervention are necessary. Analyses of panels of human or mouse cancer lines derived from the same individual that differ in their cellular phenotypes but not in genetic background have been instrumental in defining the molecular players that drive the various hallmarks of cancer. To determine the molecular regulators of metastasis in TNBC, we completed a rigorous in vitro and in vivo characterisation of four populations of the MDA-MB-231 human breast cancer line ranging in aggressiveness from non-metastatic to spontaneously metastatic to lung, liver, spleen and lymph node. Single nucleotide polymorphism (SNP) array analyses and genome-wide mRNA expression profiles of tumour cells isolated from orthotopic mammary xenografts were compared between the four lines to define both cell autonomous pathways and genes associated with metastatic proclivity. Gene set enrichment analysis (GSEA) demonstrated an unexpected association between both ribosome biogenesis and mRNA metabolism and metastatic capacity. Differentially expressed genes or families of related genes were allocated to one of four categories, associated with either metastatic initiation (e.g. CTSC, ENG, BMP2), metastatic virulence (e.g. ADAMTS1, TIE1), metastatic suppression (e.g. CST1, CST2, CST4, CST6, SCNNA1, BMP4) or metastatic avirulence (e.g. CD74). Collectively, this model system based on MDA-MB-231 cells should be useful for the assessment of gene function in the metastatic cascade and also for the testing of novel experimental therapeutics for the treatment of TNBC.This article has an associated First Person interview with the first author of the paper.

Original languageEnglish
Article number032250
Number of pages14
JournalDisease Models and Mechanisms
Volume11
Issue number5
DOIs
Publication statusPublished - 29 May 2018

Keywords

  • Breast cancer
  • Metastasis
  • Mouse model
  • Triple-negative
  • Xenograft

Cite this

Johnstone, Cameron N. ; Pattison, Andrew D. ; Gorringe, Kylie L. ; Harrison, Paul F. ; Powell, David R. ; Lock, Peter ; Baloyan, David ; Ernst, Matthias ; Stewart, Alastair G. ; Beilharz, Traude H. ; Anderson, Robin L. / Functional and genomic characterisation of a xenograft model system for the study of metastasis in triple-negative breast cancer. In: Disease Models and Mechanisms. 2018 ; Vol. 11, No. 5.
@article{abc52a8e09dc43f1b7ba1672d45b1d23,
title = "Functional and genomic characterisation of a xenograft model system for the study of metastasis in triple-negative breast cancer",
abstract = "Triple-negative breast cancer (TNBC) represents 10-20{\%} of all human ductal adenocarcinomas and has a poor prognosis relative to other subtypes. Hence, new molecular targets for therapeutic intervention are necessary. Analyses of panels of human or mouse cancer lines derived from the same individual that differ in their cellular phenotypes but not in genetic background have been instrumental in defining the molecular players that drive the various hallmarks of cancer. To determine the molecular regulators of metastasis in TNBC, we completed a rigorous in vitro and in vivo characterisation of four populations of the MDA-MB-231 human breast cancer line ranging in aggressiveness from non-metastatic to spontaneously metastatic to lung, liver, spleen and lymph node. Single nucleotide polymorphism (SNP) array analyses and genome-wide mRNA expression profiles of tumour cells isolated from orthotopic mammary xenografts were compared between the four lines to define both cell autonomous pathways and genes associated with metastatic proclivity. Gene set enrichment analysis (GSEA) demonstrated an unexpected association between both ribosome biogenesis and mRNA metabolism and metastatic capacity. Differentially expressed genes or families of related genes were allocated to one of four categories, associated with either metastatic initiation (e.g. CTSC, ENG, BMP2), metastatic virulence (e.g. ADAMTS1, TIE1), metastatic suppression (e.g. CST1, CST2, CST4, CST6, SCNNA1, BMP4) or metastatic avirulence (e.g. CD74). Collectively, this model system based on MDA-MB-231 cells should be useful for the assessment of gene function in the metastatic cascade and also for the testing of novel experimental therapeutics for the treatment of TNBC.This article has an associated First Person interview with the first author of the paper.",
keywords = "Breast cancer, Metastasis, Mouse model, Triple-negative, Xenograft",
author = "Johnstone, {Cameron N.} and Pattison, {Andrew D.} and Gorringe, {Kylie L.} and Harrison, {Paul F.} and Powell, {David R.} and Peter Lock and David Baloyan and Matthias Ernst and Stewart, {Alastair G.} and Beilharz, {Traude H.} and Anderson, {Robin L.}",
year = "2018",
month = "5",
day = "29",
doi = "10.1242/dmm.032250",
language = "English",
volume = "11",
journal = "Disease Models and Mechanisms",
issn = "1754-8403",
publisher = "The Company of Biologists",
number = "5",

}

Functional and genomic characterisation of a xenograft model system for the study of metastasis in triple-negative breast cancer. / Johnstone, Cameron N.; Pattison, Andrew D.; Gorringe, Kylie L.; Harrison, Paul F.; Powell, David R.; Lock, Peter; Baloyan, David; Ernst, Matthias; Stewart, Alastair G.; Beilharz, Traude H.; Anderson, Robin L.

In: Disease Models and Mechanisms, Vol. 11, No. 5, 032250, 29.05.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Functional and genomic characterisation of a xenograft model system for the study of metastasis in triple-negative breast cancer

AU - Johnstone, Cameron N.

AU - Pattison, Andrew D.

AU - Gorringe, Kylie L.

AU - Harrison, Paul F.

AU - Powell, David R.

AU - Lock, Peter

AU - Baloyan, David

AU - Ernst, Matthias

AU - Stewart, Alastair G.

AU - Beilharz, Traude H.

AU - Anderson, Robin L.

PY - 2018/5/29

Y1 - 2018/5/29

N2 - Triple-negative breast cancer (TNBC) represents 10-20% of all human ductal adenocarcinomas and has a poor prognosis relative to other subtypes. Hence, new molecular targets for therapeutic intervention are necessary. Analyses of panels of human or mouse cancer lines derived from the same individual that differ in their cellular phenotypes but not in genetic background have been instrumental in defining the molecular players that drive the various hallmarks of cancer. To determine the molecular regulators of metastasis in TNBC, we completed a rigorous in vitro and in vivo characterisation of four populations of the MDA-MB-231 human breast cancer line ranging in aggressiveness from non-metastatic to spontaneously metastatic to lung, liver, spleen and lymph node. Single nucleotide polymorphism (SNP) array analyses and genome-wide mRNA expression profiles of tumour cells isolated from orthotopic mammary xenografts were compared between the four lines to define both cell autonomous pathways and genes associated with metastatic proclivity. Gene set enrichment analysis (GSEA) demonstrated an unexpected association between both ribosome biogenesis and mRNA metabolism and metastatic capacity. Differentially expressed genes or families of related genes were allocated to one of four categories, associated with either metastatic initiation (e.g. CTSC, ENG, BMP2), metastatic virulence (e.g. ADAMTS1, TIE1), metastatic suppression (e.g. CST1, CST2, CST4, CST6, SCNNA1, BMP4) or metastatic avirulence (e.g. CD74). Collectively, this model system based on MDA-MB-231 cells should be useful for the assessment of gene function in the metastatic cascade and also for the testing of novel experimental therapeutics for the treatment of TNBC.This article has an associated First Person interview with the first author of the paper.

AB - Triple-negative breast cancer (TNBC) represents 10-20% of all human ductal adenocarcinomas and has a poor prognosis relative to other subtypes. Hence, new molecular targets for therapeutic intervention are necessary. Analyses of panels of human or mouse cancer lines derived from the same individual that differ in their cellular phenotypes but not in genetic background have been instrumental in defining the molecular players that drive the various hallmarks of cancer. To determine the molecular regulators of metastasis in TNBC, we completed a rigorous in vitro and in vivo characterisation of four populations of the MDA-MB-231 human breast cancer line ranging in aggressiveness from non-metastatic to spontaneously metastatic to lung, liver, spleen and lymph node. Single nucleotide polymorphism (SNP) array analyses and genome-wide mRNA expression profiles of tumour cells isolated from orthotopic mammary xenografts were compared between the four lines to define both cell autonomous pathways and genes associated with metastatic proclivity. Gene set enrichment analysis (GSEA) demonstrated an unexpected association between both ribosome biogenesis and mRNA metabolism and metastatic capacity. Differentially expressed genes or families of related genes were allocated to one of four categories, associated with either metastatic initiation (e.g. CTSC, ENG, BMP2), metastatic virulence (e.g. ADAMTS1, TIE1), metastatic suppression (e.g. CST1, CST2, CST4, CST6, SCNNA1, BMP4) or metastatic avirulence (e.g. CD74). Collectively, this model system based on MDA-MB-231 cells should be useful for the assessment of gene function in the metastatic cascade and also for the testing of novel experimental therapeutics for the treatment of TNBC.This article has an associated First Person interview with the first author of the paper.

KW - Breast cancer

KW - Metastasis

KW - Mouse model

KW - Triple-negative

KW - Xenograft

UR - http://www.scopus.com/inward/record.url?scp=85056423721&partnerID=8YFLogxK

U2 - 10.1242/dmm.032250

DO - 10.1242/dmm.032250

M3 - Article

VL - 11

JO - Disease Models and Mechanisms

JF - Disease Models and Mechanisms

SN - 1754-8403

IS - 5

M1 - 032250

ER -