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ERRalpha mediates metabolic adaptations that drive lapatinib resistance in breast cancer (gene expression profiles)

ABSTRACT: Ablation of ERRalpha significantly delays ERBB2-induced mammary tumorigenesis and ERRalpha regulates genes of the ERBB2 amplicon. To further investigate the relationship between ERRalpha activity and RTK signaling, we depleted ERRalpha in SKBr3 cells upon serum starvation, EGF treatment or heregulin treatment. Inhibition of ERBB2 signaling using the RTK inhibitor lapatinib impacts on ERRalpha stability. Since we have shown that the development of lapatinib-resistance restaures the expression of ERRalpha in breast cancer cells, we performed depletion of ERRalpha in SKBr3 cells that have developped resistance to lapatinib treatment in order to identify a potential reprogramming of ERRa transcriptional activity associated to lapatinib resistance,

ORGANISM(S): Homo sapiens

PROVIDER: GSE81546 | GEO | 2016/06/15

SECONDARY ACCESSION(S): PRJNA321920

REPOSITORIES: GEO

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Project description:This dataset is part of the manuscript titled "The metabolic regulator ERRalpha, a downstream target of HER2/IGF1, as a therapeutic target in breast cancer" (in review). The expression data obtained in human mammary epithelial cells were used to generate a list of ERRalpha-regulated genes that was later refined in clinical breast cancer datasets to generate a clinically relevant signature of ERalpha activity (referred to as Cluster 3 signature). Using this signature of the estrogen-related receptor alpha (ERRa) to profile more than eight-hundred breast tumors, we found that patients with tumors exhibiting higher ERRa activity were predicted to have shorter disease free survival. Further, the ability of an ERRa antagonist, XCT790, to inhibit breast cancer cell proliferation correlates with the cellâs intrinsic ERRa activity. These findings highlight the potential of using the ERRa signature and antagonists in targeted therapy for breast cancer. Using a chemical genomic approach we determined that activation of the HER2/IGF1 signaling pathways upregulates the expression of PGC-1b, an obligate cofactor for ERRa activity. Knockdown of PGC-1b in HER2 positive breast cancer cells impaired ERRa signaling and reduced cell proliferation, implicating a functional role of PGC1b/ERRa in the pathogenesis HER2 positive breast cancer. Primary human mammary epithelial cells were a gift from Dr. J. Marks (Duke University, Durham, NC) and cultured in MEBM (Cambrex, East Rutherford, NJ) with MEGM bullet kit and supplemented with 5mg/ml transferrin and 10-5M isoproterenol. To generate ERR-alpha signature, hMECs were serum starved for 36h followed by infection with MOI=150 of adenoviruses expressing two variants of PGC1alpha, a protein ligand for ERRalpha: PGC-1alpha2x9 or PGC-1alpha L2L3M. PGC-1-2x9 is specific to ERRalpha, while PGC-1-L2L3M lacks the NR box and does not interact with ERRalpha or other nuclear receptors. The generation and purification of variant PGC-1alpha viruses were described previously (Gaillard et al., Molecular Cell 24:5, 2006). Comparable expression levels of the two PGC-1alpha variants were verified by Western immonoblot analysis (data not shown). RNA was collect 16h after infection and purified using RNeasy mini kit (Qiagen, Valencia, CA). Ten independent biological replicates from each virus infection were collected.

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ERRalpha mediates metabolic adaptations that drive lapatinib resistance in breast cancer (gene expression profiles)

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