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01.12.2018 | Research Article | Ausgabe 1/2018 Open Access

Breast Cancer Research 1/2018

Identifying biomarkers of breast cancer micrometastatic disease in bone marrow using a patient-derived xenograft mouse model

Zeitschrift:
Breast Cancer Research > Ausgabe 1/2018
Autoren:
Sreeraj G. Pillai, Shunqiang Li, Chidananda M. Siddappa, Matthew J Ellis, Mark A. Watson, Rebecca Aft
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13058-017-0927-1) contains supplementary material, which is available to authorized users.

Abstract

Background

Disseminated tumor cells (DTCs) found in the bone marrow (BM) of patients with breast cancer portend a poor prognosis and are thought to be intermediaries in the metastatic process. To assess the clinical relevance of a mouse model for identifying possible prognostic and predictive biomarkers of these cells, we have employed patient-derived xenografts (PDX) for propagating and molecularly profiling human DTCs.

Methods

Previously developed mouse xenografts from five breast cancer patients were further passaged by implantation into NOD/SCID mouse mammary fat pads. BM was collected from long bones at early, serial passages and analyzed for human-specific gene expression by qRT-PCR as a surrogate biomarker for the detection of DTCs. Microarray-based gene expression analyses were performed to compare expression profiles between primary xenografts, solid metastasis, and populations of BM DTCs. Differential patterns of gene expression were then compared to previously generated microarray data from primary human BM aspirates from patients with breast cancer and healthy volunteers.

Results

Human-specific gene expression of SNAI1, GSC, FOXC2, KRT19, and STAM2, presumably originating from DTCs, was detected in the BM of all xenograft mice that also developed metastatic tumors. Human-specific gene expression was undetectable in the BM of those xenograft lines with no evidence of distant metastases and in non-transplanted control mice. Comparative gene expression analysis of BM DTCs versus the primary tumor of one mouse line identified multiple gene transcripts associated with epithelial-mesenchymal transition, aggressive clinical phenotype, and metastatic disease development. Sixteen of the PDX BM associated genes also demonstrated a statistically significant difference in expression in the BM of healthy volunteers versus the BM of breast cancer patients with distant metastatic disease.

Conclusion

Unique and reproducible patterns of differential gene expression can be identified that presumably originate from BM DTCs in mouse PDX lines. Several of these identified genes are also detected in the BM of patients with breast cancer who develop early metastases, which suggests that they may be clinically relevant biomarkers. The PDX model may also provide a clinically relevant system for analyzing and targeting these intermediaries of metastases.
Zusatzmaterial
Additional file 1: Table S1. Assay ids of the Taqman probes used in the study. (XLSX 9 kb)
13058_2017_927_MOESM1_ESM.xlsx
Additional file 2: Table S2. qRT-PCR validation of the expression of six transcripts of genes previously implicated in tumorigenesis and metastasis and found to be elevated at least threefold in all seven WHIM BM samples by microarray analysis. (PPTX 33 kb)
13058_2017_927_MOESM2_ESM.pptx
Additional file 3: Table S3. Complete list of transcripts with significantly different expression between DTCs and primary tumors, and metastasis and primary tumor by microarray analysis. (XLSX 532 kb)
13058_2017_927_MOESM3_ESM.xlsx
Literatur
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