Supplementary Figure 4 from miR-34a Silences c-SRC to Attenuate Tumor Growth in Triple-Negative Breast Cancer
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posted on 2023-03-30, 23:50 authored by Brian D. Adams, Vikram B. Wali, Christopher J. Cheng, Sachi Inukai, Carmen J. Booth, Seema Agarwal, David L. Rimm, Balázs Győrffy, Libero Santarpia, Lajos Pusztai, W. Mark Saltzman, Frank J. Slack<p>Figure S4, Related to Figure 5. A-F, Further characterization of c-SRC siRNA treatments in TNBC cell lines. A, Crystal violet staining of MDA-MB-231 and Hs578T cells post 15nM si-SRC and si-Neg transfection (Day 6 images, left panel), and quantification of staining abundance is shown on right panels). B, SRB results on Hs578T cell line. C, Analysis of a second siRNA to c-SRC in MDA-MB-231 cells. SRB assays are shown in the left panel and western blot analysis confirming c-SRC knockdown (72 hour post-transfection) is shown on the right panel. D, Crystal violet staining of HFF cells. E, SA-β-gal assays in the indicated cell lines 5 days after 15nM si-SRC transfection. F, miR-34a levels 72 hours after 15nM si-SRC transfection in Hs578T cells. G, Assessment of SRC mRNA levels in the indicated cell lines 72 hours after 15nM si-SRC transfection.</p>
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Yale Cancer Center and NIH
Breast Cancer Research Foundation Award
OTKA
AIRC
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- 1. DOI - Is supplement to miR-34a Silences c-SRC to Attenuate Tumor Growth in Triple-Negative Breast Cancer
ARTICLE ABSTRACT
Triple-negative breast cancer (TNBC) is an aggressive subtype with no clinically proven biologically targeted treatment options. The molecular heterogeneity of TNBC and lack of high frequency driver mutations other than TP53 have hindered the development of new and effective therapies that significantly improve patient outcomes. miRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are becoming promising therapeutic agents. We performed miRNA-profiling studies in different TNBC subtypes to identify miRNAs that significantly contribute to disease progression. We found that miR-34a was lost in TNBC, specifically within mesenchymal and mesenchymal stem cell–like subtypes, whereas expression of miR-34a targets was significantly enriched. Furthermore, restoration of miR-34a in cell lines representing these subtypes inhibited proliferation and invasion, activated senescence, and promoted sensitivity to dasatinib by targeting the proto-oncogene c-SRC. Notably, SRC depletion in TNBC cell lines phenocopied the effects of miR-34a reintroduction, whereas SRC overexpression rescued the antitumorigenic properties mediated by miR-34a. miR-34a levels also increased when cells were treated with c-SRC inhibitors, suggesting a negative feedback exists between miR-34a and c-SRC. Moreover, miR-34a administration significantly delayed tumor growth of subcutaneously and orthotopically implanted tumors in nude mice, and was accompanied by c-SRC downregulation. Finally, we found that miR-34a and SRC levels were inversely correlated in human tumor specimens. Together, our results demonstrate that miR-34a exerts potent antitumorigenic effects in vitro and in vivo and suggests that miR-34a replacement therapy, which is currently being tested in human clinical trials, represents a promising therapeutic strategy for TNBC. Cancer Res; 76(4); 927–39. ©2015 AACR.Usage metrics
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Biological Agents & TherapiesAntisense oligonucleotidesBreast CancerCarcinogenesisTumor initiation and promotionCell Death And SenescenceCellular aging and senescenceComputational MethodsGene expression profilingDrug TargetsOncoprotein & tumor suppressor drug targetsGene RegulationAntisense control of gene expressionGenome BiologySilencing and reactivation of gene expressionOncogenes & Tumor SuppressorsProgression, Invasion & MetastasisMigration and invasionTumor progression
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