Abstract
The lungs are a frequent target of metastatic breast cancer cells, but the underlying molecular mechanisms are unclear. All existing data were obtained either using statistical association between gene expression measurements found in primary tumors and clinical outcome, or using experimentally derived signatures from mouse tumor models. Here, we describe a distinct approach that consists of using tissue surgically resected from lung metastatic lesions and comparing their gene expression profiles with those from nonpulmonary sites, all coming from breast cancer patients. We show that the gene expression profiles of organ-specific metastatic lesions can be used to predict lung metastasis in breast cancer. We identified a set of 21 lung metastasis-associated genes. Using a cohort of 72 lymph node-negative breast cancer patients, we developed a 6-gene prognostic classifier that discriminated breast primary cancers with a significantly higher risk of lung metastasis. We then validated the predictive ability of the 6-gene signature in 3 independent cohorts of breast cancers consisting of a total of 721 patients. Finally, we show that the signature improves risk stratification independently of known standard clinical variables and a previously established lung metastasis signature based on an experimental breast cancer metastasis model.
Highlights
Metastasis is the main cause of death from breast cancer, reducing the chances of long-term survival from 90% to around 5% [1]
A class comparison was conducted based on an univariate t test, with a stringent P value of 10À4, to identify genes differentially expressed by the lung and the nonlung metastatic lesions
After applying filtering criteria, we identified 21 differentially expressed genes (Table 1; All genes were up-regulated with the exception of the tumor suppressor gene PTEN, which was down-regulated in lung metastases)
Summary
Metastasis is the main cause of death from breast cancer, reducing the chances of long-term survival from 90% to around 5% [1]. Breast cancer is a heterogeneous disease, with respect to many characteristics, including those associated with metastasis. Patients differ widely in prognosis and survival. Metastasis was long thought to result from a cryptic minority of tumor cells with increased metastatic capacity at the primary site [2]. Studies with genome-wide microarray techniques recently raised the concept that the clinical outcome of breast cancer. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Jackson: Division of Cell & Molecular Biology, Imperial College London, London, United Kingdom
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