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Profiling of p53-responsive genes in human breast cancer cells harboring endogenous ts-p53 E285K

ABSTRACT: The ts-p53 E285K protein is a rare p53 mutant with temperature-sensitive (ts) loss of function characteristics. In cancer cells, which express ts-p53 E285K intrinsically, endogenous wild type p53 activity is reconstituted by appropriate cultivation temperature (permissive condition). At non-appropriate cultivation temperature (restrictive condition) this p53 mutant is inactive. The present study took advantage of this mechanism and employed IPH-926 lobular breast cancer cells and BT-474 ductal breast cancer cells, which both harbor endogenous ts-p53 E285K, for the transcriptional profiling of p53-responsive genes. This new approach eliminated the need for genetic modification or cytotoxic stimulation to achive a p53 response in the cells being investigated . Three subseqent passages of IPH-926 lobular breast cancer cells (harboring ts-p53 E285K) were seeded into two parallel culture dishes each and were allowed to adopt to restrictive and permissive condition for 24 h before analysis on Affymetrix U133 Plus 2.0 microarrays. Subsequently, this experiment was repeated with BT-474 ductal breast cancer cells (also harboring ts-p53 E285K). To gate out non-specific temperature effects, the same experiment was also performed with MCF-7 breast cancer cells (harboring wt p53). Probe sets differentially expressed at restrictive versus permissive condition in MCF-7 were considered as non-specifically regulated. These probe sets were excluded from the final statistical analysis of IPH-926 and BT-474 expression data. response to restored p53 activity

ORGANISM(S): Homo sapiens

SUBMITTER: Christgen M

PROVIDER: S-ECPF-GEOD-35006 | biostudies-other | 2012 Nov

REPOSITORIES: biostudies-other

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Profiling of p53-responsive genes in human breast cancer cells harboring endogenous ts-p53 E285K

2012-12-31 | GSE35006 | GEO

Profiling of p53-responsive genes in human breast cancer cells harboring endogenous ts-p53 E285K

Project description:The ts-p53 E285K protein is a rare p53 mutant with temperature-sensitive (ts) loss of function characteristics. In cancer cells, which express ts-p53 E285K intrinsically, endogenous wild type p53 activity is reconstituted by appropriate cultivation temperature (permissive condition). At non-appropriate cultivation temperature (restrictive condition) this p53 mutant is inactive. The present study took advantage of this mechanism and employed IPH-926 lobular breast cancer cells and BT-474 ductal breast cancer cells, which both harbor endogenous ts-p53 E285K, for the transcriptional profiling of p53-responsive genes. This new approach eliminated the need for genetic modification or cytotoxic stimulation to achive a p53 response in the cells being investigated . Three subseqent passages of IPH-926 lobular breast cancer cells (harboring ts-p53 E285K) were seeded into two parallel culture dishes each and were allowed to adopt to restrictive and permissive condition for 24 h before analysis on Affymetrix U133 Plus 2.0 microarrays. Subsequently, this experiment was repeated with BT-474 ductal breast cancer cells (also harboring ts-p53 E285K). To gate out non-specific temperature effects, the same experiment was also performed with MCF-7 breast cancer cells (harboring wt p53). Probe sets differentially expressed at restrictive versus permissive condition in MCF-7 were considered as non-specifically regulated. These probe sets were excluded from the final statistical analysis of IPH-926 and BT-474 expression data. response to restored p53 activity

2012-12-31 | E-GEOD-35006 | biostudies-arrayexpress

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Transcription profiling by array of human hormone-responsive MCF-7 cells versus estrogen-deprived breast cancer cells

Project description:Estrogen deprivation using aromatase inhibitors is currently the standard of care for patients with estrogen-receptor (ER)-positive breast cancer. Unfortunately, prolonged estrogen deprivation leads to drug resistance (i.e. hormone-independent growth). We therefore used DNA microarray analysis to study the gene expression profiles of wild-type MCF-7 cells (which are sensitive to antihormone therapy) and long-term estrogen deprived MCF-7:5C and MCF-7:2A breast cancer cells (which are resistance to estrogen-deprivation; aromatase inhibitor resistant). Transcriptional profiling of wild-type MCF-7 cells and estrogen deprived MCF-7:5C and MCF-7:2A cells was performed using Affymetrix Human Genome U133 Plus 2.0 Array. Experiment Overall Design: We wanted to study the gene expression profiles of the different cell lines in their growth media without any drug treatment. Therefore, MCF-7, MCF-7:5C, and MCF-7:2A cells were grown in estrogen-free media (phenol red-free RPMI medium supplemented with 10% 4X dextran-coated charcoal-treated fetal bovine serum) until they were 70-80% confluent then RNA was extracted, labeled, and hybridized to the Affymetrix Human Genome U133 Plus 2.0 Arrays.

| S-ECPF-GEOD-10879 | biostudies-other

Transcription profiling of human breast cancer cell lines to investigate p53 status in breast cancer

Project description:Breast cancer subtypes identified in genomic studies have different underlying genetic defects. Mutations in the tumor suppressor p53 occur more frequently in estrogen receptor (ER) negative, basal-like and HER2-amplified tumors than in luminal, ER positive tumors. Thus, because p53 mutation status is tightly linked to other characteristics of prognostic importance, it is difficult to identify p53's independent prognostic effects. The relation between p53 status and subtype can be better studied by combining data from primary tumors with data from isogenic cell line pairs (with and without p53 function). In this study, the p53-dependent gene expression signatures of four cell lines (MCF-7, ZR-75-1, and two immortalized human mammary epithelial cell lines) were identified by comparing p53-RNAi transduced cell lines to their parent cell lines. Cell lines were treated with vehicle only or doxorubicin to identify p53 responses in both non-induced and induced states. Each cell line displayed unique patterns of gene expression, but cell type specific trends were evident. A common gene expression signature associated with p53 loss across all four cell lines was identified. This signature showed overlap with the signature of p53 loss in primary breast tumors and predicted relapse-free survival and overall survival in independent test data sets. Experiment Overall Design: We analyzed 48 arrays performed using 48 polyA RNA samples. RNAs were collected from cell lines treated with an IC50 dose of doxorubicin hydrochloride or with a feeding control. Each cell line had its own reference which represented the second sample on the dual channel array. These untreated RNAs were prepared by pooling four harvests of that cell line at 60-80% confluence and 48h after feeding

| S-ECPF-GEOD-3178 | biostudies-other

The Mutant p53-Targeting Compound APR-246 Induces ROS-Modulating Genes in Breast Cancer Cells.

Project description:TP53 is the most frequently mutated gene in human cancer and thus an attractive target for novel cancer therapy. Several compounds that can reactive mutant p53 protein have been identified. APR-246 is currently being tested in a phase II clinical trial in high-grade serous ovarian cancer. We have used RNA-seq analysis to study the effects of APR-246 on gene expression in human breast cancer cell lines. Although the effect of APR-246 on gene expression was largely cell line dependent, six genes were upregulated across all three cell lines studied, i.e., TRIM16, SLC7A11, TXNRD1, SRXN1, LOC344887, and SLC7A11-AS1. We did not detect upregulation of canonical p53 target genes such as CDKN1A (p21), 14-3-3σ, BBC3 (PUMA), and PMAIP1 (NOXA) by RNA-seq, but these genes were induced according to analysis by qPCR. Gene ontology analysis showed that APR-246 induced changes in pathways such as response to oxidative stress, gene expression, cell proliferation, response to nitrosative stress, and the glutathione biosynthesis process. Our results are consistent with the dual action of APR-246, i.e., reactivation of mutant p53 and modulation of redox activity. SLC7A11, TRIM16, TXNRD1, and SRXN1 are potential new pharmacodynamic biomarkers for assessing the response to APR-246 in both preclinical and clinical studies.

| S-EPMC6132178 | biostudies-literature

Selective targeting p53WT lung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA.

Project description:TP53 plays essential roles in tumor initiation and progression, and is frequently mutated in cancer. However, pharmacological stabilization and reactivation of p53 have not been actively explored for targeted cancer therapies. Herein, we identify a novel Cyclophilin A (CypA) small molecule inhibitor (HL001) that induces non-small cell lung cancer (NSCLC) cell cycle arrest and apoptosis via restoring p53 expression. We find that HL001 stabilizes p53 through inhibiting the MDM2-mediated p53 ubiquitination. Further mechanistic studies reveal that the downregulation of G3BP1 and the induction of reactive oxygen species and DNA damage by HL001 contribute to p53 stabilization. Surprisingly, HL001 selectively suppresses tumor growth in p53 wild-type NSCLC harboring Arg72 homozygous alleles (p53-72R) through disrupting interaction between MDM2 and p53-72R in a CypA-dependent manner. Moreover, combining HL001 with cisplatin synergistically enhance tumor regression in orthotopic NSCLC mouse model. Collectively, this study demonstrates that pharmacologic inhibition of CypA offers a potential therapeutic strategy via specific activation of p53-72R in NSCLC.

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Dysregulated Phosphorylation of p53, Autophagy and Stemness Attributes the Mutant p53 Harboring Colon Cancer Cells Impaired Sensitivity to Oxaliplatin.

Project description:Colorectal cancer (CRC) forms one of the highest ranked cancer types in the world with its increasing incidence and mortality rates despite the advancement in cancer therapeutics. About 50% of human CRCs are reported to have defective p53 expression resultant of TP53 gene mutation often contributing to drug resistance. The current study was aimed to investigate the response of wild-type TP53 harboring HCT 116 and mutant TP53 harboring HT 29 colon cancer cells to chemotherapeutic drug oxaliplatin (OX) and to elucidate the underlying molecular mechanisms of sensitivity/resistance in correlation to their p53 status. OX inhibited growth of wild-type p53-harboring colon cancer cells via p53/p21-Bax mediated apoptosis. Our study revealed that dysregulated phosphorylation of p53, autophagy as well as cancer stemness attributes the mutant p53-harboring colon cancer cells impaired sensitivity to OX.

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Project description:Docosahexaenoic acid (DHA) has been reported to induce tumor cell death by apoptosis. However, little is known about the effects of DHA on autophagy, another complex well-programmed process characterized by the sequestration of cytoplasmic material within autophagosomes. Here, we show that DHA increased both the level of microtubule-associated protein light-chain 3 and the number of autophagic vacuoles without impairing autophagic vesicle turnover, indicating that DHA induces not only apoptosis but also autophagy. We also observed that DHA-induced autophagy was accompanied by p53 loss. Inhibition of p53 increased DHA-induced autophagy and prevention of p53 degradation significantly led to the attenuation of DHA-induced autophagy, suggesting that DHA-induced autophagy is mediated by p53. Further experiments showed that the mechanism of DHA-induced autophagy associated with p53 attenuation involved an increase in the active form of AMP-activated protein kinase and a decrease in the activity of mammalian target of rapamycin. In addition, compelling evidence for the interplay between autophagy and apoptosis induced by DHA is supported by the findings that autophagy inhibition suppressed apoptosis and further autophagy induction enhanced apoptosis in response to DHA treatment. Overall, our results demonstrate that autophagy contributes to the cytotoxicity of DHA in cancer cells harboring wild-type p53.

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