BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells

Khaled, Walid T.; Lee, Song Choon; Stingl, John; Chen, Xiongfeng; Ali, H. Raza; Rueda, Oscar M.; Hadi, Fazal; Wang, Juexuan; Yu, Yong; Chin, Suet-Feung; Stratton, Mike; Futreal, Andy; Jenkins, Nancy A.; Aparicio, Samuel; Copeland, Neal G.; Watson, Christine J.; Caldas, Carlos; Liu, Pentao

doi:10.1038/ncomms6987

Cited by 142 publications

(167 citation statements)

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“…Khaled et al revealed a novel tumorigenic function of BCL11A in TNBC. In brief, BCL11A is highly expressed in TNBC, and exogenous BCL11A overexpression in TNBC promotes tumor development in vitro and in vivo [20]. These findings indicate that BCL11A might be a potential candidate for targeted therapy in TNBC.…”

Section: Introductionmentioning

confidence: 83%

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MiR-137 Suppresses Triple-Negative Breast Cancer Stemness and Tumorigenesis by Perturbing BCL11A-DNMT1 Interaction

Chen

Luo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Triple negative breast cancer (TNBC) is resistant to conventional chemotherapy due to high proportions of cancer stem cells (CSCs). The aim of this study is to unravel the miR-137-mediated regulatory mechanism of B-cell lymphoma/leukemia 11A (BCL11A) in TNBC. Methods: A corhort of 34 TNBC tumor tissues and paired adjacent normal tissues, as well as 25 non-TNBC tumor tissues and paired adjacent normal tissues were collected post-operatively from patients with breast cancer. Q-PCR was performed to determine the mRNA levels of miR-137 and BCL11A in breast tissues and cell lines. Bioinformatics analysis and dual luciferase reporter assay were used to verify the direct interaction between miR-137 and BCL11A. After up-/down-regulation of BCL11A, miR-137, or DNMT1 via lentiviral transduction in TNBC cell lines SUM149 and MDA-MB-231 cells, Q-PCR and Western blot assays were used to detect the expression levels of BCL11A, DNA methyltransferases 1 (DNMT1), and Islet-1 (ISL1). Mammosphere assay was conducted to assess tumorosphere formation ability of cells, coupled with flow cytometry to determine the percentage of breast cancer stem cells. Co-immunoprecipitation assay was used to determine the interaction between BCL11A and DNMT1. Xenograft tumorigenesis assay was performed to monitor tumor formation in vivo. Results: BCL11A was highly expressed in TNBC, whereas miR-137 was significantly lower in both TNBC tissues and cell lines. miR-137 suppressed BCL11A expression at both mRNA and protein levels by directly targeting its 3’UTR. In both SUM149 and MDA-MB-231 cells, overexpression of miR-137 or knockdown of BCL11A reduced the number of tumoroshperes and the percentage of cancer stem cells in vitro, and inhibited tumor development in vivo. Furthermore, BCL11A interacted with DNMT1 in TNBC cells. Silencing of either BCL11A or DNMT1 impaired cancer stemness and tumorigenesis of TNBC via suppressing ISL1 expression both in vitro, and in vivo. Conclusions: By perturbing BCL11A-DNMT1 interaction, miR-137 impairs cancer stemness and suppresses tumor development in TNBC.

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Section: Introductionmentioning

confidence: 83%

“…Previous study suggests that BCL11A acts as an oncogene in TNBC [20]. We next examined whether miR-137-mediated down-regulation of BCL11A would inhibit tumor development in TNBC cells.…”

Section: Mir-137 Inhibits Cancer Stemness Of Tnbc By Down-regulatingmentioning

confidence: 99%

MiR-137 Suppresses Triple-Negative Breast Cancer Stemness and Tumorigenesis by Perturbing BCL11A-DNMT1 Interaction

Chen

Luo

et al. 2018

Cell Physiol Biochem

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“…125,126 In principle, the genetic knockout of BCL11A by targeting BCL11A coding sequence in order to create frameshift null alleles represents a potential therapeutic strategy. Roles of BCL11A in nonhematopoietic lineages, including the neural lineage, 127,128 pancreatic progenitors, 129 and the breast epithelium, 130 would not be problematic upon modification of BCL11A in autologous CD34 1 HSPCs. However, this strategy is limited by extraerythroid roles of BCL11A in the hematopoietic system, including its requirement for B-cell development 127,[131][132][133] and HSC function.…”

Section: Bcl11a Targetingmentioning

confidence: 99%

Customizing the genome as therapy for the β-hemoglobinopathies

Canver

Orkin

2016

Blood

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Despite nearly complete understanding of the genetics of the β-hemoglobinopathies for several decades, definitive treatment options have lagged behind. Recent developments in technologies for facile manipulation of the genome (zinc finger nucleases, transcription activator-like effector nucleases, or clustered regularly interspaced short palindromic repeats–based nucleases) raise prospects for their clinical application. The use of genome-editing technologies in autologous CD34+ hematopoietic stem and progenitor cells represents a promising therapeutic avenue for the β-globin disorders. Genetic correction strategies relying on the homology-directed repair pathway may repair genetic defects, whereas genetic disruption strategies relying on the nonhomologous end joining pathway may induce compensatory fetal hemoglobin expression. Harnessing the power of genome editing may usher in a second-generation form of gene therapy for the β-globin disorders.

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“…Recently, high expression of the functionally related protein Bcl11a was reported in Triple-negative breast cancers (18). A similar analysis of Bcl11b expression in breast cancer subtypes and comparison with a Bcl11b high signature could provide some hints whether Bcl11b contributes to breast tumorigenesis.…”

mentioning

confidence: 97%

The mammary stem cell field wakes up to hibernating cells

Michalak

2017

Stem Cell Investig.

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BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells

Cited by 142 publications

References 61 publications

MiR-137 Suppresses Triple-Negative Breast Cancer Stemness and Tumorigenesis by Perturbing BCL11A-DNMT1 Interaction

MiR-137 Suppresses Triple-Negative Breast Cancer Stemness and Tumorigenesis by Perturbing BCL11A-DNMT1 Interaction

Customizing the genome as therapy for the β-hemoglobinopathies

The mammary stem cell field wakes up to hibernating cells

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