p53 is a frequent target for mutation in human tumors and previous studies have revealed that these missense mutant proteins can actively contribute to tumorigenesis. To elucidate how mutant p53 might contribute to mammary carcinogenesis we employed a three-dimensional (3D) culture model. In 3D culture non-malignant breast epithelial cells form structures reminiscent of acinar structures found in vivo, whereas breast cancer cells form highly disorganized and in some cases invasive structures. We found that mutant p53 depletion is sufficient to phenotypically revert breast cancer cells to a more acinar-like morphology. Genome-wide expression analysis identified the sterol biosynthesis, or mevalonate, pathway as significantly upregulated by a tumor-derived mutant p53. Using statins and sterol biosynthesis intermediates, we demonstrate that this pathway is both necessary and sufficient for the phenotypic effects of mutant p53 on breast tissue architecture. Mutant p53 associates with the sterol gene promoters at least partly via the SREBP transcription factors. Finally, p53 mutation correlates with higher levels of sterol biosynthesis genes in human breast tumors. This activity of mutant p53 not only contributes insight into breast carcinogenesis, but also implicates the mevalonate pathway as a new therapeutic target for tumors bearing such mutations in p53.
Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway.
Specimen part, Cell line
View SamplesThe most common oncogenic mutations in multiple myeloma (MM) affect N- and K-RAS leading to constitutive activation of RAS-dependent signaling. Signal transduction via RAS, Raf and MAPK has been well described as a canonical pathway. In accordance with this assumption, we showed that the activity of the MEK/ERK module is strictly dependent on pan-Raf activity. However, inhibition of MEK/ERK has no or only minor effects on MM cell survival, whereas oncogenic Ras and pan-Raf critically contribute to survival of multiple myeloma cells. Therefore, we aimed to learn more about Raf-dependent but MEK-independent signaling effectors.
Pan-Raf co-operates with PI3K-dependent signalling and critically contributes to myeloma cell survival independently of mutated RAS.
Cell line
View Samplessorafenib is the treatment of reference for hepatocellular carcinoma (HCC). We applied sorafenib on the human HCC cell line Huh7 and the subclone shRb, carrying a stable knock-down of the expression of the RB1 gene, a key regulator of liver carcinogenesis. Our aim was to better understand the physiologic and metabolic consequences of the exposure of HCC cells to sorafenib.
Metallothionein-1 as a biomarker of altered redox metabolism in hepatocellular carcinoma cells exposed to sorafenib.
Specimen part, Cell line, Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Global DNA Hypomethylation in Epithelial Ovarian Cancer: Passive Demethylation and Association with Genomic Instability.
Sex, Age, Specimen part, Disease stage
View SamplesComparison of DNA methylome, mRNA transcriptome, and copy number variation in tumors with global loss of DNA methylation to tumors with normal global methylation.
Global DNA Hypomethylation in Epithelial Ovarian Cancer: Passive Demethylation and Association with Genomic Instability.
Sex, Age, Specimen part, Disease stage
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Identification of tissue-specific transcriptional markers of caloric restriction in the mouse and their use to evaluate caloric restriction mimetics.
Sex, Specimen part
View SamplesThe effect of a short-term calorie restricted diet was evaluated in heart in seven strains of mice
Identification of tissue-specific transcriptional markers of caloric restriction in the mouse and their use to evaluate caloric restriction mimetics.
Sex, Specimen part
View SamplesThe effect of a short-term calorie restricted diet was evaluated in gastrocnemius muscle (GASTROC) in seven strains of mice
Identification of tissue-specific transcriptional markers of caloric restriction in the mouse and their use to evaluate caloric restriction mimetics.
Sex, Specimen part
View SamplesThe effect of a short-term calorie restricted diet was evaluated in epididymal white adipose tissue (WAT) in seven strains of mice
Identification of tissue-specific transcriptional markers of caloric restriction in the mouse and their use to evaluate caloric restriction mimetics.
Sex, Specimen part
View SamplesThe effect of a short-term calorie restricted diet was evaluated in cerebral cortex in seven strains of mice
Identification of tissue-specific transcriptional markers of caloric restriction in the mouse and their use to evaluate caloric restriction mimetics.
Sex, Specimen part
View Samples