Biallelic inactivating mutations of the transcription factor 1 gene (TCF1), encoding hepatocyte nuclear factor 1␣ (HNF1␣) were identified in 50% of hepatocellular adenomas (HCA) phenotypically characterized by a striking steatosis. To understand the molecular basis of this aberrant lipid storage, we performed a microarray transcriptome analysis validated by quantitative reverse transcription-PCR, Western blotting, and lipid profiling. In mutated HCA, we showed a repression of gluconeogenesis coordinated with an activation of glycolysis, citrate shuttle, and fatty acid synthesis predicting elevated rates of lipogenesis. Moreover, the strong down-regulation of liver fatty acid-binding protein suggests that impaired fatty acid trafficking may also contribute to the fatty phenotype. In addition, transcriptional profile analysis of the observed deregulated genes in non-HNF1␣-mutated HCA as well as in non-tumor livers allowed us to define a specific signature of the HNF1␣-mutated HCA. In these tumors, lipid composition was dramatically modified according to the transcriptional deregulations identified in the fatty acid synthetic pathway. Surprisingly, lipogenesis activation did not operate through sterol regulatory element-binding protein-1 (SREBP-1) and carbohydrate-response element-binding protein (ChREBP) that were repressed. We conclude that steatosis in HNF1␣-mutated HCA results mainly from an aberrant promotion of lipogenesis that is linked to HNF1␣ inactivation and that is independent of both SREBP-1 and ChREBP activation. Finally, our findings have potential clinical implications since lipogenesis can be efficiently inhibited by targeted therapies. Hepatocyte nuclear factor 1-␣ (HNF1␣)3 is a transcription factor that controls the expression of liver-specific genes, such as ␤-fibrinogen, ␣1-antitrypsin, and albumin (1). Heterozygous germline mutations in the gene encoding HNF1␣ (TCF1 (transcription factor 1)) are responsible for an autosomal dominant form of non-insulin-dependent diabetes mellitus called maturity onset diabetes of the young type 3 (MODY3), in which subjects usually develop hyperglycemia before 25 years of age (2). More recently, we identified HNF1␣ as a tumor suppressor gene involved in human liver tumorigenesis since we found biallelic inactivating mutations of this gene in 50% of hepatocellular adenomas (HCA) and in rare cases of well differentiated hepatocellular carcinomas developed in the absence of cirrhosis (3). HCA are rare benign primary liver tumors closely related to oral contraceptive intake (4).Recently, in a comprehensive analysis of genotype-phenotype correlations in a large series of 96 HCA, we showed that HNF1␣ mutations define a homogeneous group of tumors phenotypically characterized by the recurrent presence of a marked steatosis (5). To get insight into the underlying molecular mechanisms that drive the fatty phenotype in human HNF1␣-mutated HCA, we performed a transcriptome analysis using cDNA and Affymetrix microarrays. Gene expression profiles were compared between non-t...

Background: The molecular mechanisms underlying innate tumor drug resistance, a major obstacle to successful cancer therapy, remain poorly understood. In colorectal cancer (CRC), molecular studies have focused on drug-selected tumor cell lines or individual candidate genes using samples derived from patients already treated with drugs, so that very little data are available prior to drug treatment.

BackgroundThe PIP (prolactin-inducible protein) gene has been shown to be expressed in breast cancers, with contradictory results concerning its implication. As both the physiological role and the molecular pathways in which PIP is involved are poorly understood, we conducted combined gene expression profiling and network analysis studies on selected breast cancer cell lines presenting distinct PIP expression levels and hormonal receptor status, to explore the functional and regulatory network of PIP co-modulated genes.Principal FindingsMicroarray analysis allowed identification of genes co-modulated with PIP independently of modulations resulting from hormonal treatment or cell line heterogeneity. Relevant clusters of genes that can discriminate between [PIP+] and [PIP−] cells were identified. Functional and regulatory network analyses based on a knowledge database revealed a master network of PIP co-modulated genes, including many interconnecting oncogenes and tumor suppressor genes, half of which were detected as differentially expressed through high-precision measurements. The network identified appears associated with an inhibition of proliferation coupled with an increase of apoptosis and an enhancement of cell adhesion in breast cancer cell lines, and contains many genes with a STAT5 regulatory motif in their promoters.ConclusionsOur global exploratory approach identified biological pathways modulated along with PIP expression, providing further support for its good prognostic value of disease-free survival in breast cancer. Moreover, our data pointed to the importance of a regulatory subnetwork associated with PIP expression in which STAT5 appears as a potential transcriptional regulator.