Constitutive activation of the phosphatidylinositol-3-OH kinase (PI3K) and RAS signaling pathways are important events in tumor formation. This is illustrated by the frequent genetic alteration of several key players from these pathways in a wide variety of human cancers. Here, we report a detailed sequence analysis of the PTEN, PIK3CA, KRAS, HRAS, NRAS, and BRAF genes in a collection of 40 human breast cancer cell lines. We identified a surprisingly large proportion of cell lines with mutations in the PI3K or RAS pathways (54% and 25%, respectively), with mutants for each of the six genes. The PIK3CA, KRAS, and BRAF mutation spectra of the breast cancer cell lines were similar to those of colorectal cancers. Unlike in colorectal cancers, however, mutational activation of the PI3K pathway was mutually exclusive with mutational activation of the RAS pathway in all but 1 of 30 mutant breast cancer cell lines (P = 0.001). These results suggest that there is a fine distinction between the signaling activators and downstream effectors of the oncogenic PI3K and RAS pathways in breast epithelium and those in other tissues. (Mol Cancer Res 2007;5(2):195–201)

Significance: Our report highlights, for the first time to our knowledge, a distinct relationship between lysosomal integral membrane protein type-2 (LIMP-2) expression, β-glucocerebrosidase (GC) activity, and clearance of α-synuclein. In LIMP-2–deficient mice, increased levels of endogenous α-synuclein led to severe neurological deficits and premature death. We found that loss of LIMP-2 reduced lysosomal GC activity, resulting in lipid storage, disturbed autophagic/lysosomal function, and α-synuclein accumulation leading to neurotoxicity of dopaminergic neurons as well as apoptotic cell death and inflammation. Furthermore, heterologous overexpression of functional LIMP-2 enhanced α-synuclein clearance and improved lysosomal activity of GC. Our results suggest that lysosomal GC activity can be influenced via its interaction with LIMP-2, which could be a promising strategy for the treatment of synucleinopathies.

A biomarker is an analyte indicating the presence of a biological process linked to the clinical manifestations and outcome of a particular disease. In the case of lysosomal storage disorders (LSDs), primary and secondary accumulating metabolites or proteins specifically secreted by storage cells are good candidates for biomarkers. Clinical applications of biomarkers are found in improved diagnosis, monitoring disease progression, and assessing therapeutic correction. These are illustrated by reviewing the discovery and use of biomarkers for Gaucher disease and Fabry disease. In addition, recently developed chemical tools allowing specific visualization of enzymatically active lysosomal glucocerebrosidase are described. Such probes, coined inhibodies, offer entirely new possibilities for more sophisticated molecular diagnosis, enzyme replacement therapy monitoring, and fundamental research.