Identification of brain- and bone-specific breast cancer metastasis genes

doi:10.1016/j.canlet.2008.11.017

Cancer Letters

Volume 276, Issue 2, 18 April 2009, Pages 212-220

https://doi.org/10.1016/j.canlet.2008.11.017 Get rights and content

Abstract

In breast cancer, metastases are relatively widely distributed, with the most common sites being bone, regional lymph nodes, lung, liver, and brain. The detailed mechanism of organ-specific metastasis is poorly understood. In this study, we initiated a search for genes that are implicated in brain or bone metastasis of primary human breast cancer. We generated gene expression profiles of 18 brain and eight bone metastases derived from primary breast tumors. We identified 73 genes differentially expressed between brain and bone metastases. Visualization of the differential gene expression profiles by correspondence and cluster analyses shows that the metastases clearly separate into two distinct groups as an exact reflection of their site of metastasis. Moreover, the analysis of this gene set in primary breast tumors relapsing to either bone or brain allowed accurate categorization of the tumors according to their metastatic site. The identified genes may prove to be excellent markers to predict the site of metastasis in breast cancer patients and could lead to tailor-made therapy to an individual patient.

Introduction

Metastasis is the major reason for cancer-associated morbidity and mortality. Most patients who develop metastatic breast cancer die of their disease, with a median overall survival of 18–24 months and a 2% overall survival rate 20 years after diagnosis of metastases [1]. In breast cancer, the sites most frequently colonized are bone and lung, followed by liver and brain [2], [3]. The ability to predict their likely site of metastasis for an individual patient would allow oncologists to direct treatment plans to those patients and tissues most at risk. There is evidence that early treatment with bisphosphonates can prevent or even delay bone metastasis in breast cancer patients [4], [5]. Heretofore, only one lung-specific metastasis signature with a predictive value in a clinical setting was identified using the human breast cancer cell line MDA-MB-231 [6]. Other studies based on expression profiling of primary breast tumors relapsing to bone failed to identify a predictive signature [7]. Consequently, better tumor markers are needed to enable the assignment of metastases to their potential sites of origin.

In the present study, we decided to directly test human metastatic samples to identify tissue-specific genes for metastasis. We compared the gene expression profiles of 18 brain and eight bone metastases derived from primary breast tumors and identified 82 transcripts corresponding to 73 genes differentially expressed between these two types of metastases. Cluster and correspondence analyses performed with these genes allowed a clear distinction between brain and bone metastases. Furthermore, the expression profile of these genes permitted an accurate classification of primary breast tumors relapsing to either bone or brain according to their site of metastasis.

Section snippets

Tissues and cell lines

Eight bone metastases and three primary tumors relapsing to bone were obtained from patients who underwent surgery at the Robert-Rössle-Clinic, Berlin. The eighteen brain metastases were provided by Rita Schmutzler (University of Cologne, Germany). Tissue material was snap-frozen in liquid nitrogen after surgery. Hematoxylin and eosin (H&E)-stained sections were prepared for assessment of the percentage of tumor cells, and only samples with more than 80% tumor cells were selected for analysis.

Identification and functional characterization of genes differentially expressed between brain and bone breast cancer metastases

We applied the CorrXpression software in order to visualize the gene expression profiles of 18 brain and eight bone metastases in a two dimensional fashion and to determine the genes differentially expressed between these two types of metastases. Fig. 1 shows the 15390 expressed transcripts (yellow circles) and the position of the analyzed specimens (brain metastases-red squares, bone metastases-dark blue squares). The graph illustrates a clear separation between the two types of breast cancer

Discussion

It has long been recognized that breast cancer spreads to distant organs with a characteristic preference for regional lymph nodes, bone, liver, lung, and brain. However, using transgenic or xenograft models, it is possible to mimic only a fraction of these sites simultaneously. In addition, microarray data obtained from these models, as well as microarray profiling of primary tumors and metastases, have yielded conflicting results.

In the present study, we decided to directly test human

Acknowledgements

The authors thank Konstanze Michaelis, Gabriele Born, Ina Wendler and Frank Rösel for excellent technical assistance. We thank Jessica Wittnam and Natalia Manrique Hoyos for critical reading of the manuscript.

This work was supported by the Deutsche Krebshilfe Grant 70-2701.

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Identification of brain- and bone-specific breast cancer metastasis genes

Abstract

Introduction

Section snippets

Tissues and cell lines

Identification and functional characterization of genes differentially expressed between brain and bone breast cancer metastases

Discussion

Acknowledgements

Lancet

Cancer Cell

Curr. Opin. Struct. Biol.

Cancer Cell

Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer

J. Clin. Oncol.

Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis

Breast Cancer Res. Treat.

Breast cancer metastasis: markers and models

Nat. Rev. Cancer

Additive antitumor activities of taxoids in combination with the bisphosphonate ibandronate against invasion and adhesion of human breast carcinoma cells to bone

Int. J. Cancer

Bisphosphonate treatment and radiotherapy in metastatic breast cancer

Med. Oncol.

Genes that mediate breast cancer metastasis to lung

Nature

Genes associated with breast cancer metastatic to bone

J. Clin. Oncol.

Comparison of gene expression data from human and mouse breast cancers: identification of a conserved breast tumor gene set

Int. J. Cancer

CorrXpression – identification of significant groups of genes and experiments by means of correspondence analysis and ratio analysis

In Silico Biol.

Evaluation of S100A10, annexin II and B-FABP expression as markers for renal cell carcinoma

Cancer Sci.

A new melanoma antigen fatty acid-binding protein 7, involved in proliferation and invasion, is a potential target for immunotherapy and molecular target therapy

Cancer Res.

FABP7 expression in glioblastomas: relation to prognosis, invasion and EGFR status

J. Neurooncol.

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Nat. Rev. Mol. Cell Biol.