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| Title / Description | PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer |
| Accession | GSE64033 |
| Summary | Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors and selective PI3Kα inhibitors are in clinical development. The activity of these agents, however, is not homogenous and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling with different agents results in induction of ER-dependent transcriptional activity as demonstrated by changes in expression in genes containing ER binding sites, enhanced ER transcription and increased occupancy by the ER of promoter regions of upregulated genes. Furthermore, expression of ESR1 mRNA and ER protein levels themselves were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenograft and patient derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition. We propose that increased ER transcriptional activity may be a compensatory mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors. |
| Organism | Homo sapiens |
| Platform | GPL10558 |
| Normalized | False |
| Parsed SOFT file |
| Differential expression method | Characteristic Direction |
| Cutoff | 500 |
| Organism | Homo sapiens |
| Cell_type | MCF7cells |
| Pert_name | BYL-719 |
| Pert_id | PubChemCID:56649450 |
| Organism | human |
| Pert_type | chemical |
| Principal Component Analysis | |
| Hierarchical clustering |
| Gene lists | Enrichr | L1000CDS2 | PAEA | Crowdsourcing | |
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