Both bulk and cancer stem cell subpopulations in triple‐negative breast cancer are susceptible to Wnt, <scp>HDAC</scp>, and <scp>ER</scp>α coinhibition

Sulaiman, Andrew; Sulaiman, Brandon; Khouri, Lara; McGarry, Sarah; Nessim, Carolyn; Arnaout, Angel; Li, Xuguang; Addison, Christina L.; Dimitroulakos, Jim; Wang, Lisheng

doi:10.1002/1873-3468.12496

Cited by 32 publications

(38 citation statements)

References 44 publications

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“…Normal mammary tissues or areas containing tumor were identified by gross pathologic examinations. Approximately 2 mm cores were obtained using a sterile biopsy punch that was further sliced with a scalpel to obtain approximately 2 × 1 mm tumor slices (Dayekh et al ., ; Sulaiman et al ., ). The slices were randomized, and three slices were placed into each well of 24‐well plate and cultured in DMEM‐F12 medium supplemented with 10% FBS, 1% penicillin/streptomycin, 1 μg·mL −1 insulin, 0.5 ng·mL −1 hydrocortisol, and 3 ng·mL −1 epidermal growth factor.…”

Section: Methodsmentioning

confidence: 97%

“…Total RNA was extracted using RNeasy kit (Qiagen, Toronto, ON, Canada) and real‐time qPCR (RT‐qPCR) analysis was performed using Bio‐Rad MyiQ (Bio‐Rad) as previously described (Jia et al ., ; Sulaiman et al ., ). The conditions for RT‐qPCR reactions were one cycle at 95 °C for 20 s followed by 45 cycles at 95 °C for 3‐s and annealing at 60 °C for 30 s. Results were normalized to the housekeeping gene 18S ribosomal RNA (18S) or GAPDH.…”

Section: Methodsmentioning

confidence: 97%

“…β‐Catenin/TCF/LEF‐dependent reporter plasmid (7xTcf‐eGFP//SV40‐PuroR, 7TGP) containing seven Tcf/Lef‐binding sites and a puromycin resistance gene was a gift from Nusse (Addgene plasmid 24305). Lentiviral production was carried out as previously described (Jia et al ., ; Sulaiman et al ., ). 10‐cm dishes were seeded with 6 × 10 6 293T cells overnight.…”

Section: Methodsmentioning

confidence: 97%

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Dual inhibition of Wnt and Yes‐associated protein signaling retards the growth of triple‐negative breast cancer in both mesenchymal and epithelial states

Sulaiman

McGarry

et al. 2018

Molecular Oncology

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Triple‐negative breast cancer (TNBC), the most refractory subtype of breast cancer to current treatments, accounts disproportionately for the majority of breast cancer‐related deaths. This is largely due to cancer plasticity and the development of cancer stem cells (CSCs). Recently, distinct yet interconvertible mesenchymal‐like and epithelial‐like states have been revealed in breast CSCs. Thus, strategies capable of simultaneously inhibiting bulk and CSC populations in both mesenchymal and epithelial states have yet to be developed. Wnt/β‐catenin and Hippo/YAP pathways are crucial in tumorigenesis, but importantly also possess tumor suppressor functions in certain contexts. One possibility is that TNBC cells in epithelial or mesenchymal state may differently affect Wnt/β‐catenin and Hippo/YAP signaling and CSC phenotypes. In this report, we found that YAP signaling and CD44high/CD24−/low CSCs were upregulated while Wnt/β‐catenin signaling and ALDH+ CSCs were downregulated in mesenchymal‐like TNBC cells, and vice versa in their epithelial‐like counterparts. Dual knockdown of YAP and Wnt/β‐catenin, but neither alone, was required for effective suppression of both CD44high/CD24−/low and ALDH+ CSC populations in mesenchymal and epithelial TNBC cells. These observations were confirmed with cultured tumor fragments prepared from patients with TNBC after treatment with Wnt inhibitor ICG‐001 and YAP inhibitor simvastatin. In addition, a clinical database showed that decreased gene expression of Wnt and YAP was positively correlated with decreased ALDH and CD44 expression in patients’ samples while increased patient survival. Furthermore, tumor growth of TNBC cells in either epithelial or mesenchymal state was retarded, and both CD44high/CD24−/low and ALDH+ CSC subpopulations were diminished in a human xenograft model after dual administration of ICG‐001 and simvastatin. Tumorigenicity was also hampered after secondary transplantation. These data suggest a new therapeutic strategy for TNBC via dual Wnt and YAP inhibition.

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Section: Methodsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 97%

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Dual inhibition of Wnt and Yes‐associated protein signaling retards the growth of triple‐negative breast cancer in both mesenchymal and epithelial states

Sulaiman

McGarry

et al. 2018

Molecular Oncology

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“…Hsieh et al showed that HDAC3 was linked to CSC homeostasis by increasing β‐catenin expression through the Akt/glycogen synthase kinase 3β pathway. Other preclinical models also have shown the impact of HDACi on CSCs …”

Section: Epigeneticsmentioning

confidence: 99%

Optimizing poly (ADP‐ribose) polymerase inhibition through combined epigenetic and immunotherapy

Prasanna

Khanna

et al. 2018

Cancer Science

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Triple‐negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor survival outcomes. Currently, there are no targeted therapies available for TNBCs despite remarkable progress in targeted and immune‐directed therapies for other solid organ malignancies. Poly (ADP‐ribose) polymerase inhibitors (PARPi) are effective anticancer drugs that produce good initial clinical responses, especially in homologous recombination DNA repair‐deficient cancers. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival. Many efforts have been made to overcome PARPi resistance, mostly by targeting genes and effector proteins participating in homologous recombination that are overexpressed during PARPi therapy. Due to many known and unknown compensatory pathways, genes, and effector proteins, overlap and shared resistance are common. Overexpression of programmed cell death‐ligand 1 (PD‐L1) and cancer stem cell (CSC) sparing are novel PARPi resistance hypotheses. Although adding programmed cell death‐1 (PD‐1)/PD‐L1 inhibitors to PARPi might improve immunogenic cell death and be crucial for durable responses, they are less likely to target the CSC population that drives recurrent tumor growth. Lysine‐specific histone demethylase‐1A and histone deacetylase inhibitors have shown promising activity against CSCs. Combining epigenetic drugs such as lysine‐specific histone demethylase‐1A inhibitors or histone deacetylase inhibitors with PARPi/anti‐PD‐1/PD‐L1 is a novel, potentially synergistic strategy for priming tumors and overcoming resistance. Furthermore, such an approach could pave the way for the identification of new upstream epigenetic and genetic signatures.

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“…Also, due to the non‐expression of receptors TNBCs have an inferior prognosis. However, Sulaiman et al [] when analyzed the data from 887 invasive TNBC breast cancer patients observed an increased Wnt, HDAC that was associated with upregulation of oestrogen receptor 1 (ESR1) and repression of progesterone receptor (PGFR), more relapse and hence, reduced survival. Accordingly, one strategy by co‐suppressing Wnt, HDAC, and ESR1 in TNBC cell lines using clinically relevant low dose inhibitors could effectively repress both CSC subpopulations and cancer cells and also reverted CSCs to non‐CSC populations.…”

Section: Approaches Toward Cancer Stem Cell Therapeuticsmentioning

confidence: 99%

Breast Cancer Stem Cell Therapeutics, Multiple Strategies Versus Using Engineered Mesenchymal Stem Cells With Notch Inhibitory Properties: Possibilities and Perspectives

Bose

Sen

2017

J of Cellular Biochemistry

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Relapse cases of cancers are more vigorous and difficult to control due to the preponderance of cancer stem cells (CSCs). Such CSCs that had been otherwise dormant during the first incidence of cancer gradually appear as radiochemoresistant cancer cells. Hence, cancer therapeutics aimed at CSCs would be an effective strategy for mitigating the cancers during relapse. Alternatively, CSC therapy can also be proposed as an adjuvant therapy, along-with the conventional therapies. As regenerative stem cells (RSCs) are known for their trophic effects, anti-tumorogenicity, and better migration toward an injury site, this review aims to address the use of adult stem cells such as dental pulp derived; cord blood derived pure populations of regenerative stem cells for targeting CSCs. Indeed, pro-tumorogenicity of RSCs is of concern and hence has also been dealt with in relation to breast CSC therapeutics. Furthermore, as notch signaling pathways are upregulated in breast cancers, and anti-notch antibody based and sh-RNA based therapies are already in the market, this review focuses the possibilities of engineering RSCs to express notch inhibitory proteins for breast CSC therapeutics. Also, we have drawn a comparison among various possibilities of breast CSC therapeutics, about, notch1 inhibition. J. Cell. Biochem. 119: 141-149, 2018. © 2017 Wiley Periodicals, Inc.

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Both bulk and cancer stem cell subpopulations in triple‐negative breast cancer are susceptible to Wnt, HDAC, and ERα coinhibition

Cited by 32 publications

References 44 publications

Dual inhibition of Wnt and Yes‐associated protein signaling retards the growth of triple‐negative breast cancer in both mesenchymal and epithelial states

Dual inhibition of Wnt and Yes‐associated protein signaling retards the growth of triple‐negative breast cancer in both mesenchymal and epithelial states

Optimizing poly (ADP‐ribose) polymerase inhibition through combined epigenetic and immunotherapy

Breast Cancer Stem Cell Therapeutics, Multiple Strategies Versus Using Engineered Mesenchymal Stem Cells With Notch Inhibitory Properties: Possibilities and Perspectives

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