butterfly effect in cancer: A single base mutation can remodel the cell

Significance A single base substitution in one allele of the PIK3CA gene (encoding the catalytic subunit p110α of PI3K) in a human breast epithelial cell induces a gene expression profile that closely resembles the gene expression profile of basal breast cancer. The mutation also causes extensive remodeling of gene signatures that are not known to be connected to the activity of PI3K. The data show that a cancer-specific mutation that induces a gain of function in PI3K has an unexpectedly deep and broad impact on the phenotypic properties of the cell. 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 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.