Sulforaphane enhances the anticancer activity of taxanes against triple negative breast cancer by killing cancer stem cells

Burnett, Joseph; Lim, Gi; Li, Yanyan; Shah, Ronak B.; Lim, Rebekah; Paholak, Hayley J.; McDermott, Sean; Sun, Lichao; Tsume, Yasuhiro; Bai, Shuhua; Wicha, Max S.; Sun, Duxin; Zhang, Tao

doi:10.1016/j.canlet.2017.02.023

Cited by 113 publications

(84 citation statements)

References 66 publications

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“…Hence, we next sought to determine whether natural extracts and ITCs were able to target the CSC-like phenotype and evade cell chemoresistance by modulation of ALDH1 activity even at doses bellow extracts’ EC 50 values obtained in antiproliferative assays, as described in other studies [64,65]. More precisely, the maximum dose tested for each extract and respective ITC was an approximated value of half the extract’s EC 50 value (30 µM for SFN/broccoli extract and 60 µM PEITC/watercress extract).…”

Section: Resultsmentioning

confidence: 99%

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Pereira

Silva²,

Duarte³

et al. 2017

Nutrients

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Colorectal cancer (CRC) recurrence is often attributable to circulating tumor cells and/or cancer stem cells (CSCs) that resist to conventional therapies and foster tumor progression. Isothiocyanates (ITCs) derived from Brassicaceae vegetables have demonstrated anticancer effects in CRC, however little is known about their effect in CSCs and tumor initiation properties. Here we examined the effect of ITCs-enriched Brassicaceae extracts derived from watercress and broccoli in cell proliferation, CSC phenotype and metastasis using a previously developed three-dimensional HT29 cell model with CSC-like traits. Both extracts were phytochemically characterized and their antiproliferative effect in HT29 monolayers was explored. Next, we performed cell proliferation assays and flow cytometry analysis in HT29 spheroids treated with watercress and broccoli extracts and respective main ITCs, phenethyl isothiocyanate (PEITC) and sulforaphane (SFN). Soft agar assays and relative quantitative expression analysis of stemness markers and Wnt/β-catenin signaling players were performed to evaluate the effect of these phytochemicals in stemness and metastasis. Our results showed that both Brassicaceae extracts and ITCs exert antiproliferative effects in HT29 spheroids, arresting cell cycle at G2/M, possibly due to ITC-induced DNA damage. Colony formation and expression of LGR5 and CD133 cancer stemness markers were significantly reduced. Only watercress extract and PEITC decreased ALDH1 activity in a dose-dependent manner, as well as β-catenin expression. Our research provides new insights on CRC therapy using ITC-enriched Brassicaceae extracts, specially watercress extract, to target CSCs and circulating tumor cells by impairing cell proliferation, ALDH1-mediated chemo-resistance, anoikis evasion, self-renewal and metastatic potential.

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Section: Resultsmentioning

confidence: 99%

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Pereira

Silva²,

Duarte³

et al. 2017

Nutrients

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“…The CSCs with CD44 + /CD24 −/low subpopulations selected by flow cytometry were seeded into ultra‐low–attachment 6‐well plates (3471; Corning, Corning, NY, USA) at a density of 2000 cells per well (24). The CSCs were cultured with MammoCult Human Medium Kit (Stemcell Technologies, Vancouver, BC, Canada) according to manufacturer's instructions (25).…”

Section: Methodsmentioning

confidence: 99%

EPHA5 mediates trastuzumab resistance in HER2‐positive breast cancers through regulating cancer stem cell‐like properties

Chu

Feng

et al. 2019

FASEB j.

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Trastuzumab is a successful, rationally designed therapy that provides significant clinical benefit for human epidermal growth factor receptor‐2 (HER2)‐positive breast cancer patients. However, about half of individuals with HER2‐positive breast cancer do not respond to trastuzumab treatment because of various resistance mechanisms, including but not limited to: 1) shedding of the HER2 extracellular domain, 2) steric hindrance (e.g., MUC4 and MUC1), 3) parallel pathway activation (this is the general mechanism cited in the quote above), 4) perturbation of downstream signaling events (e.g., PTEN loss or PIK3CA mutation), and 5) immunologic mechanisms (such as FcR polymorphisms). EPHA5, a receptor tyrosine kinase, has been demonstrated to act as an anticancer agent in several cancer cell types. In this study, deletion of EPHA5 can significantly increase the resistance of HER2‐positive breast cancer patients to trastuzumab. To investigate how EPHA5 deficiency induces trastuzumab resistance, clustered regularly interspaced short palindromic repeat technology was used to create EPHA5‐deficient variants of breast cancer cells. EPHA5 deficiency effectively increases breast cancer stem cell (BCSC)‐like properties, including NANOG, CD133+, E‐cadherin expression, and the CD44+/CD24−/low phenotype, concomitantly enhancing mammosphere‐forming ability. EPHA5 deficiency also caused significant aggrandized tumor malignancy in trastuzumab‐sensitive xenografts, coinciding with the up‐regulation of BCSC‐related markers and intracellular Notch1 and PTEN/AKT signaling pathway activation. These findings highlight that EPHA5 is a potential prognostic marker for the activity of Notch1 and better sensitivity to trastuzumab in HER2‐positive breast cancer. Moreover, patients with HER2‐positive breast cancers expressing high Notch1 activation and low EPHA5 expression could be the best candidates for anti‐Notch1 therapy.—Li, Y., Chu, J., Feng, W., Yang, M., Zhang, Y., Zhang, Y., Qin, Y., Xu, J., Li, J., Vasilatos, S. N., Fu, Z., Huang, Y., Yin, Y. EPHA5 mediates trastuzumab resistance in HER2‐positive breast cancers through regulating cancer stem cell–like properties. FASEB J. 33, 4851–4865 (2019). http://www.fasebj.org

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“…Secondary spheres were used to analyze the efficiency of mammosphere-formation by assessing the number of spheres formed per cells seeded [28]. Then formed spheres were counted manually and representative images were acquired [26] using Leica DMI3000B microscope with Leica Microsystems Framework.…”

Section: Mammosphere Culturementioning

confidence: 99%

“…The cancer stem cells were plated into ultra-low attachment six well plates (corning 3471) at a density of 2000 cells per well [26]. The cancer stem cells were cultured with MammoCult TM Human Medium Kit (Stem cell technologies, Vancouver, BC, Canada) according to manufacturer's guidelines [27].…”

Section: Mammosphere Culturementioning

confidence: 99%

MiR-4319 Suppress the Malignancy of Triple-Negative Breast Cancer by Regulating Self-Renewal and Tumorigenesis of Stem Cells

Chu

Fan

et al. 2018

Cell Physiol Biochem

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Background/Aims: High levels of cancer stem cells (CSCs) in patients with triple-negative breast cancer (TNBC) correlate with risk of poor clinical outcome and possibly contribute to chemoresistance and metastasis in patients with highly malignant TNBC. Aberrant microRNA expression is associated with the dysfunction of self-renewal and proliferation in cancer stem cells, while there is little information about the TNBC-specific microRNAs in regulating CSC ability. Methods: Solexa deep sequencing was performed to detect the expression levels of TNBC or non-TNBC stem cells (CSCs) microRNAs. Mammosphere formation assay, qRT-PCR and the xenograft model in nude mice were performed. Bioinformatic analysis and microarray were used to select the target gene, and luciferase reporter assays were used to confirm the binding sites. Results: Solexa sequencing data exhibited differential expression of 193 microRNAs between TNBC and non-TNBC stem cells. The gene ontology analysis and pathways analyses showed that genes were involved in the maintenance of stemness. MiR-4319 could suppress the self-renewal and formation of tumorspheres in TNBC CSCs through E2F2, and also inhibited tumor initiation and metastasis in vivo. Moreover, increased E2F2 could reverse the effect of miR-4319 on the self-renewal in TNBC CSCs. Conclusions: MiR-4319 suppresses the malignancy of TNBC by regulating self-renewal and tumorigenesis of stem cells and might be a remarkable prognostic factor or therapeutic target for patients with TNBC.

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Sulforaphane enhances the anticancer activity of taxanes against triple negative breast cancer by killing cancer stem cells

Cited by 113 publications

References 66 publications

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

EPHA5 mediates trastuzumab resistance in HER2‐positive breast cancers through regulating cancer stem cell‐like properties

MiR-4319 Suppress the Malignancy of Triple-Negative Breast Cancer by Regulating Self-Renewal and Tumorigenesis of Stem Cells

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