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MANCR lncRNA modulates cell-cycle progression and metastasis in breastcancer cells by regulating the isoform-specific expression of nuclear Rho-GEF incis

ABSTRACT: A significant number of the genetic alterations observed in cancer patients lie within the non-protein-coding segments of the genome, including in regions coding for long noncoding RNAs (lncRNAs). LncRNAs display aberrant expression in cancer, including Breast cancer (BrCa), but the implication of their altered expression in BrCa progression remains to be elucidated. By performing a genome-wide transcriptome screen in a Triple negative BrCa (TNBC) progression isogenic 2D and 3D spheroid model, we identify >1000 lncRNAs that display aberrant expression during BrCa progression. MANCR, a chromatin-associated lncRNA, shows elevated expression in tumorigenic and metastatic TNBC. MANCR is up regulated in response to cellular stress, including DNA damage and modulates DNA repair and cell proliferation. In addition, MANCR promotes metastasis as MANCR-depleted cells show reduced cell migration, invasion and wound healing in vitro, and defects in lung colonization in Xenograft experiments in vivo. Transcriptome analyses reveal that MANCR modulates expression and pre-mRNA splicing of genes, controlling DNA repair and checkpoint. At the mechanistic level, MANCR promotes the transcription ofNet1A, a Rho-GEF and regulator DNA damage checkpoint and metastasis incis,by differential promoter usage. Further experiments suggest that MANCR regulates the expression of cancer-associated genes by titrating the levels of various chromatin and RNA-binding proteins. Thus, our results identified the metastasis-promoting activities of a MANCR in TNBC by regulating the expression of genes incis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE257538 | GEO | 2024/09/13

REPOSITORIES: GEO

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Project description:Purpose:Triple negative breast cancer (TNBC) commonly metastasizes to the brain and predicts poor prognosis with limited therapeutic options. TNBC frequently harbors BRCA mutations translating to platinum sensitivity; platinum response may be augmented by additional suppression of DNA repair mechanisms through poly(ADP-ribose)polymerase (PARP) inhibition. We evaluated brain penetrance and efficacy of Carboplatin +/- the PARP inhibitor ABT888, and investigated gene expression changes in murine intracranial (IC) TNBC models stratified by BRCA and molecular subtype status. Experimental design:Athymic mice were inoculated intra-cerebrally with BRCA-mutant: SUM149 (basal), MDA-MB-436 (claudin-low), or BRCA-wild-type: MDA-MB-468 (basal), MDA-MB-231BR (claudin-low) TNBC cells and treated with PBS control (IP, weekly), Carboplatin (50mg/kg/week, IP), ABT888 (25mg/kg/day, OG), or their combination. DNA-damage (?-H2AX) and apoptosis (cleaved-Caspase-3(cC3)) were assessed via IHC of IC tumors. Gene expression of BRCA-mutant IC tumors was measured. Results: Carboplatin+/-ABT888 significantly improved survival in BRCA-mutant IC models compared to control, but did not improve survival in BRCA-wild-type IC models. Carboplatin+ABT888 revealed a modest survival advantage versus Carboplatin in BRCA-mutant models. ABT888 yielded a marginal survival benefit in the MDA-MB-436 but not in the SUM149 model. BRCA-mutant SUM149 expression of ?-H2AX and cC3 proteins was elevated in all treatment groups compared to Control, while BRCA-wild-type MDA-MB-468 cC3 expression did not increase with treatment. Carboplatin treatment induced common gene expression changes in BRCA-mutant models.Conclusions: Carboplatin+/-ABT888 improves survival in BRCA-mutant IC TNBC models with corresponding DNA damage and gene expression changes. Combination therapy represents a promising treatment strategy for patients with TNBC brain metastases warranting further clinical investigation. reference x sample

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MANCR lncRNA modulates cell-cycle progression and metastasis in breastcancer cells by regulating the isoform-specific expression of nuclear Rho-GEF incis

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