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

ABSTRACT: Prognosis of triple-negative breast cancer (TNBC) remains poor. To identify shared and selective vulnerabilities of basal-like TNBC, the most common TNBC subtype, a directed siRNA lethality screen was performed in 7 human breast cancer cell lines, focusing on 154 previously identified dependency genes of 1 TNBC line. Thirty common dependency genes were identified, including multiple proteasome and RNA splicing genes, especially those associated with the U4/U6.U5 tri-snRNP complex (e.g., PRPF8, PRPF38A). PRPF8 or PRPF38A knockdown or the splicing modulator E7107 led to widespread intronic retention and altered splicing of transcripts involved in multiple basal-like TNBC dependencies, including protein homeostasis, mitosis, and apoptosis. E7107 treatment suppressed the growth of basal-A TNBC cell line and patient-derived basal-like TNBC xenografts at a well-tolerated dose. The antitumor response was enhanced by adding the proteasome inhibitor bortezomib. Thus, inhibiting both splicing and the proteasome might be an effective approach for treating basal-like TNBC. Mol Cancer Ther; 16(12); 2849-61. ©2017 AACR.

SUBMITTER: Chan S

PROVIDER: S-EPMC5997774 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Chan Stefanie S Sridhar Praveen P Kirchner Rory R Lock Ying Jie YJ Herbert Zach Z Buonamici Silvia S Smith Peter P Lieberman Judy J Petrocca Fabio F

Molecular cancer therapeutics 20170906 12

Prognosis of triple-negative breast cancer (TNBC) remains poor. To identify shared and selective vulnerabilities of basal-like TNBC, the most common TNBC subtype, a directed siRNA lethality screen was performed in 7 human breast cancer cell lines, focusing on 154 previously identified dependency genes of 1 TNBC line. Thirty common dependency genes were identified, including multiple proteasome and RNA splicing genes, especially those associated with the U4/U6.U5 tri-snRNP complex (e.g., <i>PRPF8 ...[more]

PMID: 28878028

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Project description:PurposeTriple-negative breast cancer (TNBC) is a type of breast cancer (BC) showing a high recurrence ratio and a low survival probability, which requires novel actionable molecular targets. The involvement of alternative splicing (AS) in TNBC promoted us to study the potential roles of AS events in the survival prognosis of TNBC patients.MethodsA total of 150 TNBC patients from The Cancer Genome Atlas (TCGA) were involved in this work. To study the effects of AS in the recurrence-free survival (RFS) prognosis of TNBC, we performed the analyses as follows. First, univariate Cox regression model was applied to identify RFS-related AS events. Their host genes were analyzed by Metascape to discover the potential functions and involved pathways. Next, least absolute shrinkage and selection operator (LASSO) method was used to select the most informative RFS-related AS events to constitute an AS risk factor for RFS prognosis, which was evaluated by Kaplan-Meier (KM) and receiver operating characteristic (ROC) curves in all the data and also in different clinical subgroups. Furthermore, we analyzed the relationships between splicing factors (SFs) and these RFS-related AS events to seek the possibility that SFs regulated AS events to influence RFS. Then, we evaluated the potential of these RFS-related AS events in the overall survival (OS) prognosis from all the above aspects.ResultsWe identified a total of 546 RFS-related AS events, which were enriched in some splicing and TNBC-associated pathways. Among them, seven RFS-related events were integrated into a risk factor, exhibiting satisfactory RFS prognosis alone and even better performance when combined with clinical tumor-node-metastasis stages. Furthermore, the correlation analysis between SFs and the seven AS events revealed the hypotheses that SRPK3 might upregulate PCYT2_44231_AA to have an effect on RFS prognosis and that three other SFs may work together to downregulate FLAD1_7874_RI to influence RFS prognosis. In addition, the seven RFS-related AS events were validated to be promising in the OS prognosis of TNBC as well.ConclusionThe abnormal AS events regulated by SFs may act as a kind of biomarker for the survival prognosis of TNBC.

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

Publications

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

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