Gene expression data from MDA-MB231 cells stably transduced with lentiviral vectors encoding a control shRNA (shscramble) or two shRNAs targeting Coco (shco2 and shco4)

ABSTRACT: Metastatic relapse of breast cancer and other tumor types usually occurs several years after surgical resection of the primary tumor. Early dissemination of tumor cells followed by an extended period of dormancy is thought to explain this prevalent clinical behavior. By using a gain-of-function retroviral cDNA screen in the mouse, we found that Coco, a secreted antagonist of TGF-beta ligands, induces solitary mammary carcinoma cells that have extravasated in the lung stroma to exit from dormancy. Mechanistic studies demonstrate that Coco awakens dormant metastasis-initiating cells by blocking stroma-derived Bone Morphogenetic Proteins. Inhibition of canonical BMP signaling reverses the commitment to differentiation of these cells and enhances their self-renewal and tumor-initiation capacity. Expression of Coco induces a discrete gene expression signature strongly associated with metastatic relapse to the lung but not to the bone or brain in primary patients’ samples. Accordi ngly, silencing of Coco does not inhibit metastasis to the bone or brain in mouse models. These findings suggest that metastasis-initiating cells require the self-renewal capability typically associated with stem cells in order to exit from dormancy and identify Coco as a master regulator of this process. The Affymetrix HG-U133A and Agilent platforms, which were used to build MSK82 [GSE2603], EMC192 [GSE12276], EMC286 [GSE2034], and NKI295 [van 't Veer et al., 2002; van de Vijver et al.,2002; Fan et al., 2006] datasets, do not contain probes for Coco, preventing a direct analysis of the correlation of the expression of Coco with metastatic relapse. We therefore examined the changes in gene expression caused by silencing of Coco in MDA-MB231 cells in vitro and used the resulting signature as a proxy of Coco expression. Compare the gene expression profile between shscramble with shCoco knockingdown MDA-MB231 cells Coco shRNA #2 corresponds to TRCN0000149666 and Coco shRNA #4 corresponds to TRCN0000148148.

ORGANISM(S): Homo sapiens

SUBMITTER: Gao H 

PROVIDER: S-ECPF-GEOD-28049 | biostudies-other | 2012 Aug

REPOSITORIES: biostudies-other