Our knowledge on tissue-and disease-specific functions of human genes is rather limited and highly context-specific. Here, we have developed a method for the comparison of mRNA expression levels of most human genes across 9,783 Affymetrix gene expression array experiments representing 43 normal human tissue types, 68 cancer types, and 64 other diseases. This database of gene expression patterns in normal human tissues and pathological conditions covers 113 million datapoints and is available from the GeneSapiens website.

TMPRSS2-ERG and other gene fusions involving ETS factors and genes with strong promoter elements are common in prostate cancer. Although ERG activation has been linked to invasive properties of prostate cancers, the precise mechanisms and pathways of ERG-mediated oncogenesis remain poorly understood. Here, we show that ERG knockdown in VCaP prostate cancer cells causes an activation of cell adhesion, resulting in strongly induced active β 1 -integrin and E-cadherin expression as well as changes in WNT signaling. These observations were corroborated by data from ERG-overexpressing nontransformed prostate epithelial cells as well as gene expression data from clinical prostate cancer samples, which both indicated a link between ERG and epithelial-to-mesenchymal transition (EMT). Upregulation of several WNT pathway members was seen in ERG-positive prostate cancers, with frizzled-4 (FZD4) showing the strongest overexpression as verified by both reverse transcription-PCR and immunostaining. Both ERG knockin and knockdown modulated the levels of FZD4 expression. FZD4 silencing could mimic the ERG knockdown phenotype by inducing active β 1 -integrin and E-cadherin expression, whereas FZD4 overexpression reversed the phenotypic effects seen with ERG knockdown. Taken together, our results provide mechanistic insights to ERG oncogenesis in prostate cancer, involving activation of WNT signaling through FZD4, leading to cancer-promoting phenotypic effects, including EMT and loss of cell adhesion. Cancer Res; 70(17); 6735-45. ©2010 AACR.

Since bone metastatic breast cancer is an incurable disease, causing significant morb idity and mortality, understanding of the underlying molecu lar mechanisms would be h ighly valuable. Here, we describe in v itro and in v ivo evidence for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic and histological observations in the inoculated mice. Geno me -wide gene exp ression profiling of th is isogenic cell line pair revealed that all the three genes involved in the L-serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) were upregulated in the highly metastatic variant. This pathway is the primary endogenous source for L-serine in mammalian t issues. Consistently, we observed that the proliferat ion of MDA -MB-231(SA) cells in serine-free conditions was dependent on PSAT1 exp ression. In addition, we observed that L-serine is essential for the fo rmation of bone resorbing human osteoclasts and may thus contribute to the vicious cycle of osteolytic bone metastasis. High expression of PHGDH and PSAT1 in primary breast cancer was significantly associated with decreased relapse-free and overall survival of patients and malignant phenotypic features of breast cancer. In conclusion, high expression of serine biosynthesis genes in metastatic breast cancer cells and the stimulating effect of L-serine on osteoclastogenesis and cancer cell pro liferat ion indicate a functionally critical role for serine biosynthesis in bone metastatic breast cancer and thereby an opportunity for targeted therapeutic interventions.

Members of the ErbB subfamily of receptor tyrosine kinases are important regulators of normal mammary gland physiology, and aberrations in their signaling have been associated with breast tumorigenesis. Therapeutics targeting epidermal growth factor receptor (EGFR = ErbB1) or ErbB2 in breast cancer have been approved for clinical use. In contrast, relatively little is known about the biological significance of ErbB4 signaling in breast cancer. This review focuses on recent advances in our understanding about the role of ErbB4 in breast carcinogenesis, as well as in the potential clinical relevance of ErbB4 in breast cancer prognostics and therapy.