Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Knock-in of PIK3CA-H1047R into MCF-10A

ABSTRACT: We have compared the proteome, transcriptome and metabolome of two isogenic cell lines: MCF-10A, derived from human breast epithelium, and the mutant MCF-10A-H1047R. These cell lines differ by a single amino acid substitution (H1047R) caused by single nucleotide change in one allele of the PIK3CA gene which encodes the catalytic subunit p110Î± of phosphatidylinositol 3-kinase (PI3K). The H1047R mutation of PIK3CA is one of the most frequently encountered somatic cancer-specific mutations. In MCF-10A, this mutation induces an extensive cellular reorganization that far exceeds the known signaling activities of PI3K. The changes are highly diverse; with examples in structural protein levels, the DNA repair machinery and sterol synthesis. Gene set enrichment analysis reveals a highly significant concordance of the genes differentially expressed in MCF-10A-H1047R cells and the established protein and RNA signatures of basal breast cancer. No such concordance was found with the specific gene signatures of other histological types of breast cancer. Our data document the power of a single base mutation, inducing an extensive remodeling of the cell toward the phenotype of a specific cancer. 2 cell lines (H1047R and WT), 4 time points (0, 6, 12, 24 hours), 3 replicates

ORGANISM(S): Homo sapiens

SUBMITTER: Jonathan Hart

PROVIDER: E-GEOD-63452 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Publications

The butterfly effect in cancer: a single base mutation can remodel the cell.

Hart Jonathan R JR Zhang Yaoyang Y Liao Lujian L Ueno Lynn L Du Lisa L Jonkers Marloes M Yates John R JR Vogt Peter K PK

Proceedings of the National Academy of Sciences of the United States of America 20150112 4

We have compared the proteome, transcriptome, and metabolome of two cell lines: the human breast epithelial line MCF-10A and its mutant descendant MCF-10A-H1047R. These cell lines are derived from the same parental stock and differ by a single amino acid substitution (H1047R) caused by a single nucleotide change in one allele of the PIK3CA gene, which encodes the catalytic subunit p110α of PI3K (phosphatidylinositol 3-kinase). They are considered isogenic. The H1047R mutation of PIK3CA is one of ...[more]

PMID: 25583473

Similar Datasets

Project description:Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes1-3. Pik3ca and p53 are the two most frequently mutated genes and are associated with different types of human breast cancers4. The cellular origin and the mechanisms leading to Pik3ca-induced tumour heterogeneity remain unknown. Here, we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and its impact on tumour heterogeneity. Surprisingly, oncogenic Pik3ca-H1047R expression at physiological levels5 in basal cells (BCs) using K5CREERT2 induced the formation of luminal ER+PR+ tumours, while its expression in luminal cells (LCs) using K8CREERT2 gave rise to luminal ER+PR+ tumours or basal-like ER-PR- tumours. Concomitant deletion of p53 and expression of Pik3ca-H1047R accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca-H1047R in unipotent BCs gave rise to luminal-like cells, while its expression in unipotent LCs gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that have undergone cell fate transition upon Pik3ca-H1047R expression in unipotent progenitors demonstrate a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures, characteristic of the different cell fate switches that occur upon Pik3ca-H1047R expression in BC and LCs, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca-H1047R activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation. Luminal and basal cells, or tumour cells, from mice in which expression of PIK3CA-H1047R and YFP (and in some conditions loss of p53) was targeted in basal cells using K5CREERT2 or in luminal cells using K8CREERT2 were FACS isolated and RNA was extracted before being hybridized Affymetrix microarrays.

Dataset Information

Knock-in of PIK3CA-H1047R into MCF-10A

Publications

The butterfly effect in cancer: a single base mutation can remodel the cell.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets