Identification of clinically relevant gene sets and pathways using functional models of breast tumor suppression
KeywordsBreast Cancer Breast Tumor Breast Cancer Cell Line Human Chromosome Estrogen Receptor Status
Several lines of evidence suggest that chromosome 8 is likely to harbor tumor suppressor gene(s) involved in breast cancer. We have shown previously that microcell-mediated transfer of human chromosome 8 into the breast cancer cell line MDA-MB-231 results in reversion of tumorigenicity of these cells and is accompanied by expression changes of a clinically relevant set of genes.
In the present study we demonstrate that the transfer of human chromosome 8 into another breast cancer cell line, CAL51, results in hybrids characterized by suppression of tumorigenicity in vitro and in vivo as compared with the parental cells. Loss of the transferred chromosome 8 results in reappearance of the CAL51 phenotype. Oligonucleotide microarray analysis identified 78 probe sets differentially expressed in the hybrids as compared with CAL51 and the rerevertant cells. The majority of these genes is involved in signal transduction, developmental processes, angiogenesis, cadherin signaling, Wnt signaling or inflammation.
It is of particular interest that the 78-gene signature is also reflected in a panel of breast tumors, lymph node and distant metastases, and is correlated with several prognostic markers including tumor size, grading, metastatic behavior and estrogen receptor status.
As opposed to the corresponding non-tumorigenic phenotypes demonstrated for the MDA-MB-231-derived and CAL51-derived microcell hybrids, the respective differentially expressed genes strongly differ from each other. However, it was of special interest that the majority of genes of both gene sets could be integrated into a similar spectrum of biological processes and pathways.
Our findings provide an experimental system to identify and evaluate genes but, more importantly, signatures of biological processes and pathways involved in the development and/or progression of breast cancer.