May 2007
Among prominent characteristics of the tumor microenvironment, the impact of lactic acidosis on tumor progression, alone and in its interactions with hypoxia and other environmental features, is poorly understood. We have developed genome-scale gene expression studies that aim to systemically dissect the transcriptional responses of primary breast epithelial cells to lactic acidosis and hypoxia in vitro, and to explore and quantify how these responses are linked to tumor clinical phenotypes in vivo. Statistical analysis underlying these results involves careful accounting for differences in microarray gene expression data sets, combining experimental signature derivation in vitro with the projection of such signatures to a heterogeneous set of breast cancer samples from published studies. We find that lactic acidosis elicits expression responses dominated by acidosis and that are apparently unrelated to hypoxia, and that it plays a role as an independent and significant biomarker of good prognosis in tumor progression. These novel and surprising findings improve our understanding of the different and apparently contrary roles played by key characteristics of the tumor microenvironment, as well as providing a direction for potential therapeutic investigations.
The manuscript will be available here shortly.
Supplementary Material is available as follows: