TBX3 promotes progression of pre‐invasive breast cancer cells by inducing EMT and directly up‐regulating SLUG

Krstic, Milica; Kolendowski, Bart; Cecchini, Matthew J.; Postenka, Carl O.; Hassan, Haider M.; Andrews, Joseph; MacMillan, Connor D.; Williams, Karla C.; Leong, Hon S.; Brackstone, Muriel; Torchia, Joseph; Chambers, Ann F.; Tuck, Alan B.

doi:10.1002/path.5245

Cited by 31 publications

(26 citation statements)

References 46 publications

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“…The transition to invasive and metastatic subpopulations consists of changes in tumor cells function. 12 To attain these characteristics, morphogenetic transformations, known as EMT, is in an active state that maintains the balance between epithelial phenotype and stemness feature. 13 The application of 3D culture system could mimic to some extents the in vivo conditions.…”

Section: Resultsmentioning

confidence: 99%

Hollow Alginate-Poly-L-Lysine-Alginate Microspheres Promoted an Epithelial-Mesenchymal Transition in Human Colon Adenocarcinoma Cells

et al. 2019

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Purpose: Today, there is an urgent need to develop a three-dimentional culture systems mimicking native in vivo condition in order to screen potency of drugs and possibly any genetic alterations in tumor cells. Due to the existence of limitations in animal models, the development of three dimensional systems is highly recommended. To this end, we encapsulated human colon adenocarcinoma cell line HT29 with alginate-poly-L-lysine (Alg-PLL) microspheres and the rate of epithelial-mesenchymal transition was monitored. Methods: Cells were randomly divided into three groups; control, alginate and Alg-PLL. To encapsulate cells, we mixed HT-29 cells (1 × 106 ) with 1 mL of 0.05% PLL and 1% Alg mixture and electrosprayed into CaCl2 solution by using a high-voltage power. Cells from all groups were maintained at 37˚C in a humidified atmosphere containing 5% CO2 for 7 days. Cell viability was assessed by MTT assay. To monitor the stemness feature, we measured the transcription of genes such as Snail, Zeb, and Vimentin by using real-time PCR analysis. Results: Addition of PLL to Alg in a hallowed state increased the cell survival rate compared to the control and Alg groups (P<0.05). Cells inside Alg-PLL tended to form microcellular aggregates while in Alg microspheres an even distribution of HT-29 cells was found. Real-time PCR analysis showed the up-regulation of Snail, Zeb, and Vimentin in Alg-PLL microspheres compared to the other groups, showing the acquisition of stemness feature (P<0.05). Conclusion: This study showed that hallow Alg-PLL microspheres increased the epithelialmesenchymal transition rate after 7 days in in vitro condition. Such approaches could be touted as appropriate in vitro models for drug screening.

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Section: Resultsmentioning

confidence: 99%

Hollow Alginate-Poly-L-Lysine-Alginate Microspheres Promoted an Epithelial-Mesenchymal Transition in Human Colon Adenocarcinoma Cells

et al. 2019

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“…Slug is an important transcriptional factor regulating expression of genes responsible for the EMT. [32][33] Slug had been demonstrated to down-regulate epithelial markers such as E-cadherin as well as the upregulation of mesenchymal markers such as vimentin and bronectin. Moreover, Liu Yang et al [21][22] identi ed a positive correlation between Btbd7 and Slug expression in SACC tissues; silencing BTBD7 down-regulated the expression of SLUG in SACC-LM cells which subsequently supressed the migration and invasion abilities of SACC cells.…”

Section: Discussionmentioning

confidence: 99%

High BTBD7 Expression Positive Correlated with SLUG Predicted Poor Prognosis in Hormone Receptor Negative Breast Cancer

Huang

Luo

et al. 2020

Preprint

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There is a poor prognosis of metastasis in hormone receptor negative breast cancer (HRNBC), including triple-negative breast cancer (TNBC) and HER-2 overexpression breast cancer. Recent studies have indicated that BTB/POZ domain-containing protein 7 (BTBD7) regulates SLUG which is a key EMT (epithelial-mesenchymal transformation)-associated protein. The role of BTBD7 in HRNBC, however, has not been identified. In this study, The Cancer Genome Atlas (TCGA) was used to identify BTBD7 mRNA expression in breast cancer. In addition, GO and Metascape were used to identify differentially expressed genes. Immunohistochemical staining were applied to determine the protein expression of Btbd7 and Slug in paraffin-embedded samples from 144 HRNBC patients and 30 benign lesion patients. In cancer tissue, 64.9% in TNBC and 70.0% in HER-2+ overexpression breast cancer of Btbd7 protein was expressed when compared with a 20% expression in benign lesion tissues. Increased Btbd7 expression was further associated with larger tumor volume and poor TNM stages in HRNBC patients. Higher BTBD7 mRNA expression level was associated with shorter disease free survival (DFS) time from TCGA data. Higher Btbd7 protein expression in HRNBC tissue was associated with shorter DFS and OS time. Btbd7 protein expression significantly correlated with Slug expression in HRNBC tissue. Combining Btbd7 and Slug expression had a high predictive value for 3-year and 5-year DFS. As such, the positive expression of Btbd7 may contribute towards the development of breast cancer, specifically HRNBC via the up-regulation of Slug expression. Btbd7 was concluded to be an important predictor for the diagnosis of HRNBC patients.

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“…RNA-Seq data from 21NT + EV, 21NT + TBX3iso1, and 21NT + TBX3iso2 cell lines previously published by our group [19] was used to examine differences in resultant transcriptional profiles with overexpression of TBX3iso1 and TBX3iso2 (GEO accession number: GSE126153). Assessment of differentially expressed genes was conducted by compiling a list of genes significantly up or downregulated (>1.5-fold, FDR < 0.05) in only one isoform relative to the empty vector control, or showed opposite patterns between isoforms (>1.5-fold up in one, >1.5-fold down in the other, all FDR < 0.05).…”

Section: Bioinformatics Analysesmentioning

confidence: 99%

“…The differential tumorigenicity between TBX3 isoforms was a striking and unanticipated observation. In order to assess transcriptional differences that may explain these novel findings, we re-examined our RNA-Seq dataset of TBX3iso1 and TBX3iso2 transfectant cells [19]. Interestingly, the cell lines had distinct expression signatures and clustering patterns ( Fig.…”

Section: Tbx3iso1 Promotes Angiogenesis In Vivo and In Vitromentioning

confidence: 99%

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

Krstic

Hassan

Kolendowski

et al. 2020

Laboratory Investigation

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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.

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TBX3 promotes progression of pre‐invasive breast cancer cells by inducing EMT and directly up‐regulating SLUG

Cited by 31 publications

References 46 publications

Hollow Alginate-Poly-L-Lysine-Alginate Microspheres Promoted an Epithelial-Mesenchymal Transition in Human Colon Adenocarcinoma Cells

Hollow Alginate-Poly-L-Lysine-Alginate Microspheres Promoted an Epithelial-Mesenchymal Transition in Human Colon Adenocarcinoma Cells

High BTBD7 Expression Positive Correlated with SLUG Predicted Poor Prognosis in Hormone Receptor Negative Breast Cancer

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

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