Function of RasGRP3 in the formation and progression of human breast cancer.

[severe combined immunodeficiency]

Ras guanine nucleotide exchange factors (RasGEFs ) mediate the activation of the Ras signaling pathway that is over activated in many human cancers . The RasGRP 3 , an activator of H-Ras and R-Ras protein exerts oncogenic effects and the overexpression of the protein is observed in numerous malignant cancer types . Here , we investigated the putative alteration of expression and potential function of RasGRP 3 in the formation and progression of human breast cancer .The RasGRP 3 and phosphoRasGRP 3 expressions were examined in human invasive ductal adenocarcinoma derived samples and cell lines (BT -474 , JIMT-1 , MCF 7 , SK-BR -3 , MDA-MB -453 , T -47 D ) both in mRNA (Q-PCR ) and protein (Western blot ; immunohistochemistry ) levels . To explore the biological function of the protein , RasGRP 3 knockdown cultures were established . To assess the role of RasGRP 3 in the viability of cells , annexin-V /PI staining and MitoProbe â„¢ DilC 1 (5 ) assay were performed . To clarify the function of the protein in cell proliferation and in the development of chemotherapeutic resistance , CyQuant assay was performed . To observe the RasGRP 3 function in tumor formation , the Severe combined immunodeficiency (SCID ) mouse model was used . To investigate the role of the protein in Ras-related signaling Q-PCR and Western blot experiments were performed .R asGRP 3 expression was elevated in human breast tumor tissue samples as well as in multiple human breast cancer cell lines . Down-regulation of RasGRP 3 expression in breast cancer cells decreased cell proliferation , induced apoptosis in MCF 7 cells , and sensitized T -47 D cells to the action of drugs Tamoxifen and trastuzumab (Herceptin ). Gene silencing of RasGRP 3 reduced tumor formation in mouse xenografts as well . Inhibition of RasGRP 3 expression also reduced Akt , ERK 1 /2 and estrogen receptor alpha phosphorylation downstream from IGF-I insulin like growth factor -I (IGF-I ) or epidermal growth factor (EGF ) stimulation confirming the functional role of RasGRP 3 in the altered behavior of these cells .Taken together , our results suggest that the Ras activator RasGRP 3 may have a role in the pathological behavior of breast cancer cells and may constitute a therapeutic target for human breast cancer .

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Diseases presenting "functional role" symptom

aromatase deficiency

holt-oram syndrome

primary hyperoxaluria type 1

severe combined immunodeficiency

triple a syndrome

wolf-hirschhorn syndrome

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