A network of clinically and functionally relevant genes is involved in the reversion of the tumorigenic phenotype of MDA-MB-231 breast cancer cells after transfer of human chromosome 8

Abstract

Several investigations have supposed that tumor suppressor genes might be located on human chromosome 8. We used microcell-mediated transfer of chromosome 8 into MDA-MB-231 breast cancer cells and generated independent hybrids with strongly reduced tumorigenic potential. Loss of the transferred chromosome results in reappearance of the malignant phenotype. Expression analysis identified a set of 109 genes (CT8-ps) differentially expressed in microcell hybrids as compared to the tumorigenic MDA-MB-231 and rerevertant cells. Of these, 44.9% are differentially expressed in human breast tumors. The expression pattern of CT8-ps was associated with prognostic factors such as tumor size and grading as well as loss of heterozygosity at the short arm of chromosome 8. We identified CT8-ps networks suggesting that these genes act cooperatively to cause reversion of tumorigenicity in MDA-MB-231 cells. Our findings provide a conceptual basis and experimental system to identify and evaluate genes and gene networks involved in the development and/or progression of breast cancer.

Reprogramming of the transcriptome in a novel chromosome 3 transfer tumor suppressor ovarian cancer cell line model affected molecular networks that are characteristic of ovarian cancer

“…An approach to identify differentially expressed genes associated with molecular pathways relevant in carcinogenesis is to integrate expression results generated by the comparative analysis of cancer samples, with those generated in manipulated cancer cell line models in which tumorigenicity has been affected. In a recent study of tumor suppression due to microcell mediated transfer of chromosome 8 into a breast cancer cell line, the transcriptome analysis of the resulting hybrids identified genes that were also transcriptionally modified in human breast tumors 23. Similar studies have been conducted with chromosome 17 transfer in another breast cancer cell line 24 and transfer of chromosome 11 into an ovarian cancer cell line 25, where selected genes that were altered by chromosome transfer, were also altered in tumor samples.…”

The manipulation of chromosomes by mankind: the uses of microcell-mediated chromosome transfer

“…Excitingly, potential tumour suppressor genes for ovarian cancer have been found on chromosome 22 (22q11-q12) (Kruzelock et al 2000), chromosome 3 (Rimessi et al 1994), chromosome 6 (6q27) (Acquati et al 2001) and chromosome 11 (Cao et al 2001), the latter study has led to the proposition of THY1 being a tumour suppressor gene for ovarian cancer (Abeysinghe et al 2003(Abeysinghe et al , 2004. Further, genes contained on chromosome 6 (Negrini et al 1994) and the short arm of chromosome 8 have been shown, by MMCT studies, to be important in breast cancer (Wilson et al 2003;Seitz et al 2005) and colorectal cancer (Flanagan et al 2004). Indeed, it is now evident that a network of genes all found on chromosome 8 are important for the control of tumourigenicity in breast cancer cells (Seitz et al 2005).…”

“…Further, genes contained on chromosome 6 (Negrini et al 1994) and the short arm of chromosome 8 have been shown, by MMCT studies, to be important in breast cancer (Wilson et al 2003;Seitz et al 2005) and colorectal cancer (Flanagan et al 2004). Indeed, it is now evident that a network of genes all found on chromosome 8 are important for the control of tumourigenicity in breast cancer cells (Seitz et al 2005). Chromosome 8 also contains genes that reverse cancerous phenotype in rat prostate cancer cells (Nihei et al 1996(Nihei et al , 2002 as does chromosome 20 (20p11.23-12) (Goodarzi et al 2001).…”

Expression of the protein phosphatase 1 inhibitor KEPI is downregulated in breast cancer cell lines and tissues and involved in the regulation of the tumor suppressor EGR1 via the MEK-ERK pathway

“…The preparation of tissue sample cRNA was as previously described (Seitz et al, 2005). The study was performed with the approval of the local ethics committees.…”