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Histone deacetylase inhibition in triple-negative breast cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE92911 | GEO | 2017/02/14

SECONDARY ACCESSION(S): PRJNA358777

REPOSITORIES: GEO

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Project description:IntroductionOf the more than one million global cases of breast cancer diagnosed each year, approximately fifteen percent are characterized as triple-negative, lacking the estrogen, progesterone, and Her2/neu receptors. Lack of effective therapies, younger age at onset, and early metastatic spread have contributed to the poor prognoses and outcomes associated with these malignancies. Here, we investigate the ability of the histone deacetylase inhibitor panobinostat (LBH589) to selectively target triple-negative breast cancer (TNBC) cell proliferation and survival in vitro and tumorigenesis in vivo.MethodsTNBC cell lines MDA-MB-157, MDA-MB-231, MDA-MB-468, and BT-549 were treated with nanomolar (nM) quantities of panobinostat. Relevant histone acetylation was verified by flow cytometry and immunofluorescent imaging. Assays for trypan blue viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) proliferation, and DNA fragmentation were used to evaluate overall cellular toxicity. Changes in cell cycle progression were assessed with propidium iodide flow cytometry. Additionally, qPCR arrays were used to probe MDA-MB-231 cells for panobinostat-induced changes in cancer biomarkers and signaling pathways. Orthotopic MDA-MB-231 and BT-549 mouse xenograft models were used to assess the effects of panobinostat on tumorigenesis. Lastly, flow cytometry, ELISA, and immunohistochemical staining were applied to detect changes in cadherin-1, E-cadherin (CDH1) protein expression and the results paired with confocal microscopy in order to examine changes in cell morphology.ResultsPanobinostat treatment increased histone acetylation, decreased cell proliferation and survival, and blocked cell cycle progression at G2/M with a concurrent decrease in S phase in all TNBC cell lines. Treatment also resulted in apoptosis induction at 24 hours in all lines except the MDA-MB-468 cell line. MDA-MB-231 and BT-549 tumor formation was significantly inhibited by panobinostat (10 mg/kg/day) in mice. Additionally, panobinostat up-regulated CDH1 protein in vitro and in vivo and induced cell morphology changes in MDA-MB-231 cells consistent with reversal of the mesenchymal phenotype.ConclusionsThis study revealed that panobinostat is overtly toxic to TNBC cells in vitro and decreases tumorigenesis in vivo. Additionally, treatment up-regulated anti-proliferative, tumor suppressor, and epithelial marker genes in MDA-MB-231 cells and initiated a partial reversal of the epithelial-to-mesenchymal transition. Our results demonstrate a potential therapeutic role of panobinostat in targeting aggressive triple-negative breast cancer cell types.

Project description:BackgroundTriple-negative breast cancer (TNBC) is characterized by high malignancy, strong invasiveness, and a propensity for distant metastasis, leading to poor prognosis and relatively limited treatment options. Metformin, as a first-line oral hypoglycemic agent, has garnered widespread research interest in recent years due to its potential in cancer prevention and treatment. However, its efficacy varies significantly across different tumor types. Histone deacetylase inhibitors (HDACi), such as SAHA, have demonstrated antitumor activity, but TNBC responds poorly to HDACi monotherapy, possibly due to feedback activation of the JAK-STAT pathway. Exploring the synergistic potential and underlying mechanisms of combining metformin with HDACi in TNBC treatment is crucial.MethodsWe predicted the synergistic effects of metformin and SAHA in TNBC using multiple computational methods (CMap, DTsyn, and DrugComb). We also developed a cancer-specific compound mimic library (CDTSL) and applied a three-step strategy to identify genes fitting the "metformin sensitization" model. Subsequently, we evaluated the synergistic effects of metformin and SAHA in TNBC cell lines through cell proliferation, colony formation, and apoptosis assays. Furthermore, we investigated the molecular mechanisms of the combined treatment using techniques such as transcriptome sequencing, chromatin immunoprecipitation (ChIP), Western blotting, and measurement of extracellular acidification rate (ECAR). Additionally, we assessed the in vivo antitumor effects of the combined therapy in a nude mouse subcutaneous xenograft model.ResultsCMap, DTsyn, and DrugComb all predicted the synergistic effects of SAHA and metformin in TNBC. The screening results revealed that HDAC10 played a key role in metformin sensitization. We found that the combination of metformin and SAHA exhibited synergistic antitumor effects (combination index CI < 0.9) in TNBC cell lines. Mechanistically, metformin inhibited histone acetylation on FGFR4, thereby blocking the feedback activation of FGFR4 downstream pathways induced by SAHA. Furthermore, metformin interfered with the glycolysis process induced by SAHA, altering the metabolic reprogramming of tumor cells. In in vivo experiments, the combined treatment of metformin and SAHA significantly inhibited the growth of subcutaneous tumors in nude mice.ConclusionsMetformin enhances the sensitivity of TNBC to HDAC inhibitors by blocking the FGFR4 pathway and interfering with metabolic reprogramming. When used in combination with SAHA, metformin exhibits synergistic antitumor effects. Our study provides a theoretical basis for the combined application of HDAC inhibitors and metformin, potentially offering a new strategy for the treatment of TNBC.

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Histone deacetylase inhibition in triple-negative breast cancer

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