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PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer

ABSTRACT: Overcoming cellular growth restriction, including the evasion of cellular senescence, is a hallmark of cancer. We report that PAK4 is overexpressed in all human breast cancer subtypes and associated with poor patient outcome. In mice, MMTV-PAK4 overexpression promotes spontaneous mammary cancer, while PAK4 gene depletion delays MMTV-PyMT driven tumors. Importantly, PAK4 prevents senescence-like growth arrest in breast cancer cells in vitro, in vivo and ex vivo, but is not needed in non-immortalized cells, while PAK4 overexpression in untransformed human mammary epithelial cells abrogates H-Ras-V12-induced senescence. Mechanistically, a PAK4 – RELB - C/EBPa axis controls the senescence-like growth arrest and a PAK4 phosphorylation residue (RELB-Se151) is critical for RELB-DNA interaction, transcriptional activity and expression of the senescence regulator C/EBPa. These findings establish PAK4 as a promoter of breast cancer that can overcome oncogene-induced senescence and reveal a selective vulnerability of cancer to PAK4 inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE112817 | GEO | 2019/07/09

REPOSITORIES: GEO

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PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer

Project description:PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer

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Shp2 Signaling Suppresses Senescence in PyMT-induced Mammary Gland Cancer in Mice [Mouse430_2 array]

Project description:In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated ?-gal (SA-?-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, Focal adhesion kinase and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies which rely on senescence induction by inhibiting Shp2 or controlling its target gene products may be useful in blocking breast cancer. Primary mammary tumor cells from MMTV-PyMT mice were cultured as mammospheres for 10 days and then treated with specific inhibitors of Notch (DAPT), MEK1 (U0126), FAK (TAE226), or Src (PP2) for another 2 days. Mammospheres were then subjected to RNA isolation. Each group contains 3 replicates.

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Shp2 Signaling Suppresses Senescence in PyMT-induced Mammary Gland Cancer in Mice [Mouse430A_2 array]

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Project description:MicroRNAs (miRNAs) are small, non-coding, endogenous RNAs involved in many human diseases including breast cancer. miRNA expression profiling of human breast cancers has identified miRNAs related to the clinical diversity of the disease and potentially provides novel diagnostic and prognostic tools for breast cancer therapy. In order to further understand the roles of miRNAs in association with oncogenic drivers and in specifying sub-types of breast cancer, we performed miRNAexpression profiling on mammary tumors from eight well-characterized genetically -engineered Mouse (GEM) models of human breast cancer including MMTV–H-Ras, -Her2/neu, -c-Myc, -PymT, –Wnt1 and C3(1)/SV40 T/t-antigen transgenic mice, BRCA1fl/fl;p53+/-;MMTV-cre and the p53fl/fl ;MMTV-cre transplant model. miRNA expression data for 41 mouse primary mammary tumors and 5 mouse normal mammary glands

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Genomic Profiling of mouse mammary tumor models identifies miRNA signatures associated with mammary tumor lineage (mammary normal and tumors in different mice strains)

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P21-activated kinase group II small compound inhibitor GNE-2861 perturbs estrogen receptor alpha signaling and restores tamoxifen-sensitivity in breast cancer cells

Project description:Estrogen receptor alpha (ERα) is highly expressed in most breast cancers. Consequently, ERα modulators, such as tamoxifen, are successful in breast cancer treatment, although tamoxifen resistance is commonly observed. While tamoxifen resistance may be caused by altered ERα signaling, the molecular mechanisms regulating ERα signaling and tamoxifen resistance are not entirely clear. Here, we found that PAK4 expression was consistently correlated to poor patient outcome in endocrine treated and tamoxifen-only treated breast cancer patients. Importantly, while PAK4 overexpression promoted tamoxifen resistance in MCF-7 human breast cancer cells, pharmacological treatment with a group II PAK (PAK4, 5, 6) inhibitor, GNE-2861, sensitized tamoxifen resistant MCF-7/LCC2 breast cancer cells to tamoxifen. Mechanistically, we identified a regulatory positive feedback loop, where ERα bound to the PAK4 gene, thereby promoting PAK4 expression, while PAK4 in turn stabilized the ERα protein, activated ERα transcriptional activity and ERα target gene expression. Further, PAK4 phosphorylated ERα-Ser305, a phosphorylation event needed for the PAK4 activation of ERα-dependent transcription. In conclusion, PAK4 may be a suitable target for perturbing ERα signaling and tamoxifen resistance in breast cancer patients.

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