Basal-A Triple-Negative Breast Cancer Cells Selectively Rely on RNA Splicing for Survival

Chan, Stefanie; Sridhar, Praveen; Kirchner, Rory; Lock, Ying Jie; Herbert, Zach; Buonamici, Silvia; Smith, Peter G.; Lieberman, Judy; Petrocca, Fabio

doi:10.1158/1535-7163.mct-17-0461

Cited by 43 publications

(41 citation statements)

References 35 publications

(48 reference statements)

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“…Proteasome inhibition by bortezomib (BZ; Velcade; PS-341) and carfilzomib (CZ), developed for its ability to inhibit transcription of NFκB-dependent anti-apoptotic genes, has been effective in treating multiple myeloma and other hematological malignancies [ 8 – 11 ]. By contrast, as single agents, proteasome inhibitors (PI) have failed to show a significant clinical activity in solid tumors, including TNBC [ 12 – 17 ], but the responsible mechanisms are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Proteasome inhibition induces IKK-dependent interleukin-8 expression in triple negative breast cancer cells: Opportunity for combination therapy

et al. 2018

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Triple negative breast cancer (TNBC) cells express increased levels of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8), which promotes their proliferation and migration. Because TNBC patients are unresponsive to current targeted therapies, new therapeutic strategies are urgently needed. While proteasome inhibition by bortezomib (BZ) or carfilzomib (CZ) has been effective in treating hematological malignancies, it has been less effective in solid tumors, including TNBC, but the mechanisms are incompletely understood. Here we report that proteasome inhibition significantly increases expression of IL-8, and its receptors CXCR1 and CXCR2, in TNBC cells. Suppression or neutralization of the BZ-induced IL-8 potentiates the BZ cytotoxic and anti-proliferative effect in TNBC cells. The IL-8 expression induced by proteasome inhibition in TNBC cells is mediated by IκB kinase (IKK), increased nuclear accumulation of p65 NFκB, and by IKK-dependent p65 recruitment to IL-8 promoter. Importantly, inhibition of IKK activity significantly decreases proliferation, migration, and invasion of BZ-treated TNBC cells. These data provide the first evidence demonstrating that proteasome inhibition increases the IL-8 signaling in TNBC cells, and suggesting that IKK inhibitors may increase effectiveness of proteasome inhibitors in treating TNBC.

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Section: Introductionmentioning

confidence: 99%

Proteasome inhibition induces IKK-dependent interleukin-8 expression in triple negative breast cancer cells: Opportunity for combination therapy

et al. 2018

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“…Similarly, spliceosomal proteins can be subject to recurrent somatic mutations or aberrant expression in many cancers (Dvinge et al 2016), and even perturbation of snRNP biogenesis has been implicated in oncogenesis (Koh et al 2015). Breast cancer likewise displays subtype-specific dependencies on the abundance of distinct components of the spliceosome (Hsu et al 2016;Chan et al 2018). These studies suggest that the repertoire of splicing factors that play regulatory roles may be substantially larger than is currently realized and that such factors play important roles in both healthy and malignant cells.…”

mentioning

confidence: 99%

RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing

et al. 2019

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Alternative splicing of pre-mRNAs plays a pivotal role during the establishment and maintenance of human cell types. Characterizing the transacting regulatory proteins that control alternative splicing has therefore been the focus of much research. Recent work has established that even core protein components of the spliceosome, which are required for splicing to proceed, can nonetheless contribute to splicing regulation by modulating splice site choice. We here show that the RNA components of the spliceosome likewise influence alternative splicing decisions. Although these small nuclear RNAs (snRNAs), termed U1, U2, U4, U5, and U6 snRNA, are present in equal stoichiometry within the spliceosome, we found that their relative levels vary by an order of magnitude during development, across tissues, and across cancer samples. Physiologically relevant perturbation of individual snRNAs drove widespread gene-specific differences in alternative splicing but not transcriptome-wide splicing failure. Genes that were particularly sensitive to variations in snRNA abundance in a breast cancer cell line model were likewise preferentially misspliced within a clinically diverse cohort of invasive breast ductal carcinomas. As aberrant mRNA splicing is prevalent in many cancers, we propose that a full understanding of such dysregulated pre-mRNA processing requires study of snRNAs, as well as protein splicing factors. Together, our data show that the RNA components of the spliceosome are not merely basal factors, as has long been assumed. Instead, these noncoding RNAs constitute a previously uncharacterized layer of regulation of alternative splicing, and contribute to the establishment of global splicing programs in both healthy and malignant cells.

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“…(Sørlie et al, 2001(Sørlie et al, , 2003. SNRPD1 and SRSF2 function in splicing (Bermingham et al, 1995) which was linked to survival of multiple basal-like breast cancer cell lines (Chan et al, 2017). CBX3 and ECT2 were correlated with poor prognosis (Liang et al, 2017;Wang et al, 2018).…”

Section: Unsupervised Clustering With Predicted Functional Targets Rementioning

confidence: 99%

Functionally Coherent Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling

et al. 2018

Preprint

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Cell identity is governed by gene expression, regulated by Transcription Factor (TF) binding at cisregulatory modules. We developed the NetNC software to decode the relationship between TF binding and the regulation of cognate target genes in cell decision-making; demonstrated on nine datasets for the Snail and Twist TFs, and also modENCODE 'HOT' regions. Results illuminated conserved molecular networks controlling development and disease, with implications for precision medicine. Predicted 'neutral' TF binding accounted for the majority (50% to ≥80%) of candidate target genes from statistically significant peaks and HOT regions had high functional coherence.Expression of orthologous functional TF targets discriminated breast cancer molecular subtypes and predicted novel tumour biology. We identified new gene functions and network modules including crosstalk with notch signalling and regulation of chromatin organisation, evidencing networks that reshape Waddington's landscape during epithelial remodelling. Predicted invasion roles were validated using a tractable cell model, supporting our computational approach.

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Basal-A Triple-Negative Breast Cancer Cells Selectively Rely on RNA Splicing for Survival

Cited by 43 publications

References 35 publications

Proteasome inhibition induces IKK-dependent interleukin-8 expression in triple negative breast cancer cells: Opportunity for combination therapy

Proteasome inhibition induces IKK-dependent interleukin-8 expression in triple negative breast cancer cells: Opportunity for combination therapy

RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing

Functionally Coherent Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling

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