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Proline Glutamic acid and Leucine rich Protein 1 (PELP1) promotes glioblastoma progression by enhancing Wnt/β-catenin signaling

ABSTRACT: We examined the transcriptional changes modulated by Proline Glutamic acid and Leucine rich Protein 1 (PELP1) by performing global transcriptome analysis. U87 cells were transfected with control siRNA or PELP1 siRNA and the RNA was isolated and utilized for RNA-seq analysis. Our results demonstrated that PELP1 modulated genes were related to inhibition of matrix metalloproteases, glioma invasion signaling, Wnt/β-catenin signaling and other pathways related to invasion and GBM signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131502 | GEO | 2020/04/24

REPOSITORIES: GEO

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Proline Glutamic acid and Leucine rich Protein 1 (PELP1) promotes glioblastoma progression by enhancing Wnt/β-catenin signaling

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Project description:Progesterone and estrogen are important drivers of breast cancer proliferation. Herein, we probed estrogen receptor-α (ER) and progesterone receptor (PR) cross-talk in breast cancer models. Stable expression of PR-B in PR-low/ER+ MCF7 cells increased cellular sensitivity to estradiol and insulin-like growth factor 1 (IGF1), as measured in growth assays performed in the absence of exogenous progestin; similar results were obtained in PR-null/ER+ T47D cells stably expressing PR-B. Genome-wide microarray analyses revealed that unliganded PR-B induced robust expression of a subset of estradiol-responsive ER target genes, including cathepsin-D (CTSD). Estradiol-treated MCF7 cells stably expressing PR-B exhibited enhanced ER Ser167 phosphorylation and recruitment of ER, PR and the proline-, glutamate- and leucine-rich protein 1 (PELP1) to an estrogen response element in the CTSD distal promoter; this complex co-immunoprecipitated with IGF1 receptor (IGFR1) in whole-cell lysates. Importantly, ER/PR/PELP1 complexes were also detected in human breast cancer samples. Inhibition of IGF1R or phosphoinositide 3-kinase blocked PR-B-dependent CTSD mRNA upregulation in response to estradiol. Similarly, inhibition of IGF1R or PR significantly reduced ER recruitment to the CTSD promoter. Stable knockdown of endogenous PR or onapristone treatment of multiple unmodified breast cancer cell lines blocked estradiol-mediated CTSD induction, inhibited growth in soft agar and partially restored tamoxifen sensitivity of resistant cells. Further, combination treatment of breast cancer cells with both onapristone and IGF1R tyrosine kinase inhibitor AEW541 was more effective than either agent alone. In summary, unliganded PR-B enhanced proliferative responses to estradiol and IGF1 via scaffolding of ER-α/PELP1/IGF1R-containing complexes. Our data provide a strong rationale for targeting PR in combination with ER and IGF1R in patients with luminal breast cancer.

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