scholarly journals EZH2 Inhibition Sensitizes BRCA1-Deficient Breast Cancer to Synthetic Lethal Therapy with ATM Inhibitors

2021 ◽  
Author(s):  
Leonie Ratz ◽  
Chiara Brambillasca ◽  
Leandra Bartke ◽  
Marieke van de Ven ◽  
Natalie Proost ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Synthetic Lethality ◽  
Molecular Subtype ◽  
Combined Treatment ◽  
Breast Tumors ◽  
Mammary Tumors ◽  
Genotoxic Stress ◽  
Synthetic Lethal

Abstract Background: The majority of BRCA1-mutant breast cancers are characterized by a triple-negative phenotype (TNBC) and a basal-like molecular subtype, associated with aggressive clinical behavior. Current treatment options are limited, highlighting the need for the development of novel targeted therapies for this tumor subtype. Methods: Our group previously showed that EZH2 is functionally relevant in BRCA1-deficient breast tumors and blocking EZH2 enzymatic activity could be a potent treatment strategy. To validate the role of EZH2 as a therapeutic target and to identify new synergistic drug combinations, we performed a high-throughput drug combination screen in various cell lines derived from BRCA1-proficient and deficient - mouse mammary tumors. Results: We identified the combined inhibition of EZH2 and the proximal DNA damage response kinase ATM as a novel synthetic lethality-based therapy for the treatment of BRCA1-deficient breast tumors. We show that the combined treatment with the EZH2 inhibitor GSK126 and the ATM inhibitor AZD1390 led to reduced colony formation, increased genotoxic stress, and apoptosis-mediated cell death in BRCA1-deficient mammary tumor cells in vitro. These findings were corroborated by in vivo experiments showing that simultaneous inhibition of EZH2 and ATM significantly increased anti-tumor activity in mice bearing BRCA1-deficient mammary tumors. Conclusion: Taken together, we identified a synthetic lethal interaction between EZH2 and ATM and propose this synergistic interaction as a novel molecular combination for the treatment of BRCA1-mutant breast cancer.

scholarly journals GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers

2020 ◽  
Author(s):  
Gaia Bianco ◽  
Mairene Coto-Llerena ◽  
John Gallon ◽  
Stephanie Taha-Mehlitz ◽  
Venkatesh Kancherla ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Synthetic Lethality ◽  
Poor Response ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Synthetic Lethal ◽  
Er Positive

SummarySynthetic lethal interactions, where the simultaneous but not individual inactivation of two genes is lethal to the cell, have been successfully exploited to treat cancer. GATA3 is frequently mutated in estrogen receptor (ER)-positive breast cancers and its deficiency defines a subset of patients with poor response to hormonal therapy and poor prognosis. However, GATA3 is not targetable. Here we show that GATA3 and MDM2 are synthetically lethal in ER-positive breast cancer. Depletion and pharmacological inhibition of MDM2 induce apoptosis in GATA3-deficient models in vitro, in vivo and in patient-derived organoids (PDOs) harboring GATA3 somatic mutation. The synthetic lethality requires p53 and acts via the PI3K/Akt/mTOR pathway. Our results present MDM2 as a novel therapeutic target in the substantial cohort of ER-positive, GATA3-mutant breast cancer patients. With MDM2 inhibitors widely available, our findings can be rapidly translated into clinical trials to evaluate in-patient efficacy.

scholarly journals Isoform-specific promotion of breast cancer tumorigenicity by TBX3 involves induction of angiogenesis

2019 ◽  
Vol 100 (3) ◽  
pp. 400-413
Author(s):  
Milica Krstic ◽  
Haider M. Hassan ◽  
Bart Kolendowski ◽  
M. Nicole Hague ◽  
Pieter. H. Anborgh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Subtype ◽  
Xenograft Model ◽  
Tumor Formation ◽  
Transcriptional Analysis ◽  
Breast Cancer Cell Lines ◽  
Tumor Vascularity ◽  
Mouse Xenograft Model

Abstract TBX3 is a member of the highly conserved family of T-box transcription factors involved in embryogenesis, organogenesis and tumor progression. While the functional role of TBX3 in tumorigenesis has been widely studied, less is known about the specific functions of the different isoforms (TBX3iso1 and TBX3iso2) which differ in their DNA-binding domain. We therefore sought to investigate the functional consequence of this highly conserved splice event as it relates to TBX3-induced tumorigenesis. By utilizing a nude mouse xenograft model, we have identified differential tumorigenic potential between TBX3 isoforms, with TBX3iso1 overexpression more commonly associated with invasive carcinoma and high tumor vascularity. Transcriptional analysis of signaling pathways altered by TBX3iso1 and TBX3iso2 overexpression revealed significant differences in angiogenesis-related genes. Importantly, osteopontin (OPN), a cancer-associated secreted phosphoprotein, was significantly up-regulated with TBX3iso1 (but not TBX3iso2) overexpression. This pattern was observed across three non/weakly-tumorigenic breast cancer cell lines (21PT, 21NT, and MCF7). Up-regulation of OPN in TBX3iso1 overexpressing cells was associated with induction of hyaluronan synthase 2 (HAS2) expression and increased retention of hyaluronan in pericellular matrices. These transcriptional changes were accompanied by the ability to induce endothelial cell vascular channel formation by conditioned media in vitro, which could be inhibited through addition of an OPN neutralizing antibody. Within the TCGA breast cancer cohort, we identified an 8.1-fold higher TBX3iso1 to TBX3iso2 transcript ratio in tumors relative to control, and this ratio was positively associated with high-tumor grade and an aggressive molecular subtype. Collectively, the described changes involving TBX3iso1-dependent promotion of angiogenesis may thus serve as an adaptive mechanism within breast cancer cells, potentially explaining differences in tumor formation rates between TBX3 isoforms in vivo. This study is the first of its kind to report significant functional differences between the two TBX3 isoforms, both in vitro and in vivo.

Using epigenetic reprogramming to target triple-negative breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14565-e14565
Author(s):  
D. Sharma ◽  
B. B. Knight ◽  
R. Yacoub ◽  
T. Liu ◽  
L. Taliaferro-Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Combined Treatment ◽  
Brdu Incorporation ◽  
Breast Cancers

e14565 Background: The outcome for patients with breast cancer has been significantly improved by the use of targeted agents. The prognosis of triple negative (TN) breast cancers, which do not express hormone receptors (ER, PR) or Her2, is poor, because of an aggressive clinical course and lack of targeted therapeutic agents. Epigenetic silencing of specific genes has been observed in breast cancer and some of these genes are more important due to available targeted therapies such as ER. Since all endocrine therapies are designed to block ER function in some way, the identification of new therapies or strategies that could sensitize TN breast cancers to existing endocrine therapy could provide a revolutionary means of treating this aggressive subtype of cancer Methods: We examined the efficacy of combined treatment of HDAC inhibitor LBH589 and DNMT inhibitor decitabine to regenerate ER and PR in TN breast cancer cells using RT-PCR and immunoblotting. Changes in growth and proliferation of TN breast cancer cells in response to LBH589 and decitabine treatment were determined by XTT, BrdU incorporation and colony formation assay. Changes in apoptotic proteins were determined by western blotting. Athymic nude mice were used to establish pre-clinical models for TN breast cancer cells and effectiveness of combined treatment of LBH589 and decitabine was determined. Tumors biopsies were analyzed for ER and PR re-expression by western blot analysis and immunohistochemistry at the end of the treatment. Results: Combined treatment of LBH589 and decitabine resulted in re-expression of ER and PR in TN breast cancers in vitro and in vivo. Although re-expression of ER and PR were noted following LBH589 treatment alone, re-expression was more robust with the combination. TN breast cancer cells showing re-expressed ER can be targeted with tamoxifen. Tamoxifen inhibits growth of TN breast cancer cells re- expressing ER by triggering apoptosis. Conclusions: The importance of epigenetic events such as DNA methylation and HDAC inhibition in tumor progression is becoming increasingly evident. A trial evaluating the ability of LBH589 and decitabine to re- express ER, which can then be targeted by tamoxifen, is planned in patients with metastatic TN breast cancer. No significant financial relationships to disclose.

scholarly journals Synthetic lethality-based prediction of anti-SARS-CoV-2 targets

2021 ◽  
Author(s):  
Lipika R. Pal ◽  
Kuoyuan Cheng ◽  
Nishanth U Nair ◽  
Laura Martin-Sancho ◽  
Sanju Sinha ◽  
...  
Keyword(s):  
Drug Targets ◽  
Synthetic Lethality ◽  
Host Cells ◽  
Synthetic Lethal ◽  
Viral Propagation ◽  
In Vivo Testing ◽  
Altered Gene ◽  
Host Genes

Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal (SL) partners of such altered host genes. Pursuing this antiviral strategy, here we comprehensively analyzed multiple in vitro and in vivo bulk and single-cell RNA-sequencing datasets of SARS-CoV-2 infection to predict clinically relevant candidate antiviral targets that are SL with altered host genes. The predicted SL-based targets are highly enriched for infected cell inhibiting genes reported in four SARS-CoV-2 CRISPR-Cas9 genome-wide genetic screens. Integrating our predictions with the results of these screens, we further selected a focused subset of 26 genes that we experimentally tested in a targeted siRNA screen using human Caco-2 cells. Notably, as predicted, knocking down these targets reduced viral replication and cell viability only under the infected condition without harming non-infected cells. Our results are made publicly available, to facilitate their in vivo testing and further validation.

scholarly journals Chidamide Combined With Doxorubicin Induced p53-Driven Cell Cycle Arrest and Cell Apoptosis Reverse Multidrug Resistance of Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Lixia Cao ◽  
Shaorong Zhao ◽  
Qianxi Yang ◽  
Zhendong Shi ◽  
Jingjing Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Apoptosis ◽  
Combined Treatment ◽  
Tunel Staining ◽  
Cell Cycle Distribution ◽  
Cycle Arrest

The multidrug-resistant (MDR) phenotype is usually accompanied by an abnormal expression of histone deacetylase (HDAC). Given that HDAC is vital in chromatin remodeling and epigenetics, inhibiting the role of HDAC has become an important approach for tumor treatment. However, the effect of HDAC inhibitors on MDR breast cancer has not been elucidated. This study aim to demonstrate the potential of chidamide (CHI) combined with the chemotherapy drug doxorubicin (DOX) to overcome chemotherapeutic resistance of breast cancer in vitro and in vivo, laying the experimental foundation for the next clinical application. The results showed that, CHI combined with DOX showed significant cytotoxicity to MDR breast cancer cells in vitro and in vivo compared with the CHI monotherapy. The cell cycle distribution results showed that CHI caused G0/G1 cell cycle arrest and inhibited cell growth regardless of the addition of DOX. At the same time, annexin V staining and TUNEL staining results showed that CHI enhanced the number of cell apoptosis in drug-resistant cells. The western blot analysis found that p53 was activated in the CHI-treated group and combined treatment group, and then the activated p53 up-regulated p21, apoptosis regulator recombinant protein (Puma), and pro-apoptotic protein Bax, down-regulated the apoptotic proteins Bcl-xL and Bcl-2, and activated the caspase cascade to induce apoptosis.

Synthetic-lethal interactions between ATR inhibition and functional genetic and proteomic biomarkers to predict responses in endometriosis-associated cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18000-e18000
Author(s):  
Oren Gilad ◽  
Dansu Li ◽  
Erin George ◽  
Rakesh Chettier ◽  
Fiona Simpkins ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
In Vivo Studies ◽  
Multiple Cancer ◽  
Driver Genes ◽  
Synthetic Lethal ◽  
Cancer Driver ◽  
Synthetic Lethal Interactions ◽  
Synthetically Lethal

e18000 Background: Endometriosis is a common gynecologic disorder proven to be a precursor to several cancer types. We developed a potent and selective inhibitor (ATRN-119) of a critical DNA damage response (DDR) protein kinase: the ataxia telangiectasia and Rad3-related protein (ATR). Treatment with ATRN-119 is synthetically lethal with multiple cancer-associated changes in DDR pathways, representing a new and effective strategy to treat cancer. The objective of this study is to evaluate the overlap of DDR genes that respond to ATRN-119 and those mutated in endometriosis. Methods: We sequenced the exomes of 2,932 unrelated women with surgically-confirmed endometriosis (GERMLINE) and 274 tissue blocks containing endometriosis lesions (LESION). DNA was extracted using standard methods. Missense and truncation variants were analyzed. These data were compared to analysis of a whole proteome screen for factors that respond to exposure to ATRN-119 and may influence responsiveness to treatment. Factors observed in both methods were considered high-priority biomarker candidates and were experimentally tested for synthetic lethality with ATRN-119 treatment. Results: Analysis of endometriosis patients found 89% of the LESION samples had 2 or more DDR mutations vs 83% of the GERMLINE samples. There is an excess of DDR mutations per sample in LESION (5.5 mutations) vs GERMLINE (3.89 mutations) [p = 4.66x10-6, Mann Whitney test]. In parallel, we identified 92 genes as protein responders to ATRN-119 treatment. Mutations in 21 of these 92 genes show nominal association with surgical endometriosis (p < 0.05). However, of these responsive genes, 18 are known TIER 1 cancer-driver genes and well-characterized mutations were found in three dominant genes in the LESION tissue (ATM, DDB1, and ARID1A). Overall 20% of the patients who’s LESION we examined subsequently developed an endometriosis-associated cancer. Both in vitro and in vivo studies confirmed synthetic-lethal interactions between ATRN-119 treatment and alteration of these genes. Conclusions: The overlap between DDR genes responding to ATRN-119 and those mutated in endometriosis-associated cancer suggest that genetic markers underlying response and resistance will be critical to extend the use of these drugs while increasing efficacy and minimizing toxicities. Furthermore, our data support the inclusion of endometriosis-associated cancer patients in planned ATRN-119 clinical trials.

scholarly journals In VitroCytotoxicity andIn VivoAntimammary Tumor Effects of the Hydroethanolic Extract ofAcacia seyal(Mimosaceae) Stem Bark

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Stephane Zingue ◽  
Amstrong Nang Njuh ◽  
Alain Brice Tueche ◽  
Jeremie Tamsa ◽  
Edwige Nana Tchoupang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Tumors ◽  
Stem Bark ◽  
Control Group ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Hydroethanolic Extract ◽  
Acacia Seyal

The present study was designed to evaluate thein vitroandin vivoantitumor effects ofA. seyalhydroethanolic extract on breast cancer. The cytotoxicity ofA. seyalextract was evaluated using resazurin reduction assay in 9 cell lines. Further, the protective effect of the hydroethanolic extract ofA. seyalstem barks was evaluated on 7,12-dimethylbenz(a)anthracene- (DMBA-) induced breast cancer rat model. Incidence, burden, volume, and histological analysis of mammary tumors were measured. TheAcacia seyalextract exhibited CC50of 100 in MCF-7 cells after 24 h.In vivo, no tumors were detected in rats from the control group, while 11 rats out of 12 (91.66%) developed mammary tumors in the DMBA-exposed group receiving only the vehicle.Acacia seyalextract significantly (p<0.01) and in the dose-dependent manner reduced tumor incidence (3 rats out of 12 at the dose of 300 mg/kg), burden [62.1% (150 mg/kg) and 65.8% (300 mg/kg)], and mass. It protected rats against DMBA-induced breast hyperplasia, with an optimal effect at the dose of 300 mg/kg. Taken altogether, these results suggest that the hydroethanolic extract ofAcacia seyalmight contain phytoconstituents endowed with antitumoral properties, which could protect against the breast cancer induced in rats.

scholarly journals Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Stephin J Vervoort ◽  
Olivier G de Jong ◽  
M Guy Roukens ◽  
Cynthia L Frederiks ◽  
Jeroen F Vermeulen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Poor Prognosis ◽  
Target Gene ◽  
Gene Selection ◽  
Mammary Tumorigenesis ◽  
Breast Tumors ◽  
Transcriptional Analysis

The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the type of tumor. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and can thereby promote tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways.

scholarly journals Skeletal muscle reprogramming by breast cancer regardless of treatment history or tumor molecular subtype

2019 ◽  
Author(s):  
Hannah E. Wilson ◽  
David A. Stanton ◽  
Cortney Montgomery ◽  
Aniello M. Infante ◽  
Matthew Taylor ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Molecular Subtype ◽  
Clinical History ◽  
Muscle Gene Expression ◽  
Treatment History ◽  
Muscle Gene

ABSTRACTIncreased susceptibility to fatigue is a negative predictor of survival commonly experienced by women with breast cancer. Here, we sought to identify molecular changes induced in human skeletal muscle by BC regardless of treatment history or tumor molecular subtype using RNA-sequencing and proteomic analyses. Mitochondrial dysfunction was apparent across all molecular subtypes, with the greatest degree of transcriptomic changes occurring in women with HER2/neu-overexpressing tumors, though muscle from patients of all subtypes exhibited similar pathway-level dysregulation. Interestingly, we found no relationship between anti-cancer treatments and muscle gene expression, suggesting that fatigue is a product of BC per se rather than clinical history. In vitro and in vivo experimentation confirmed the ability of BC cells to alter mitochondrial function and ATP content in muscle. These data suggest that interventions supporting muscle in the presence of BC-induced mitochondrial dysfunction may alleviate fatigue and improve the lives of women with BC.

Sign in / Sign up

Export Citation Format

Share Document