Proliferation-associated Brn-3b transcription factor can activate cyclin D1 expression in neuroblastoma and breast cancer cells

Budhram-Mahadeo, Vishwanie; Irshad, Shazia; Bowen, Samantha; Lee, S A; Samady, Laila; Tonini, Gian Paolo; Latchman, David S.

doi:10.1038/sj.onc.1210621

Cited by 21 publications

(31 citation statements)

References 38 publications

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“…It responds directly to mitogenic signals, and plays a critical role in cellcycle progression, especially during transition from G1 to the S phase [18]. Cyclin D1 has a rate-limiting role in G1-S phase transition, and plays a key role in malignant cell proliferation [45,46]. Our results indicated that c-myc and cyclin D1 were significantly downregulated by Wnt/β-catenin signaling when neuroblastoma cells proliferation was inhibited by WIF-1 restoration.…”

Section: Discussionmentioning

confidence: 68%

Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma

et al. 2014

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Neuroblastoma is the most common extracranial solid tumor in childhood and is associated with serious morbidity and mortality. The effective treatment of neuroblastoma remains one of the major challenges in pediatric oncology. The Wnt signaling pathway has been shown to play a significant role in the pathogenesis of adult and pediatric tumors. WIF-1 has been identified as an important Wnt antagonist which inhibits Wnt/β-catenin signaling by directly binding to Wnt proteins. However, the expression and function of WIF-1 in neuroblastoma remains unknown. The present study showed that WIF-1 was downregulated with high level promoter methylation in neuroblastoma cells, and was significantly upregulated after exposure to demethylating agent. This finding suggests that downregulation of WIF-1 was associated with its promoter methylation in neuroblastoma. To further study the potential function of WIF-1 in neuroblastoma, we constructed a plasmid that over-expressed WIF-1 and transfected the plasmid into one neuroblastoma cell line SK-N-SH. We found that restoration of WIF-1 inhibited the growth and proliferation of neuroblastoma cells in vitro. Morever, Wnt/β-catenin signaling activity and target genes expression were reduced by WIF-1 restoration. These results provide support that WIF-1 is downregulated and functions as a tumor suppressor by antagonizing Wnt/β-catenin signaling in neuroblastoma, suggesting a potential role as a therapeutic target in neuroblastoma.

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Section: Discussionmentioning

confidence: 68%

Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma

et al. 2014

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“…For instance, Brn-3b may enhance proliferation by increasing transcription of cell cycle regulators, cyclinD1/ CDK4 (Budhram-Mahadeo et al 2008;Samady et al 2004) whilst inhibiting the tumour suppressor gene BRCA1 (Budhram-Mahadeo et al 1999), which induces cell cycle arrest in breast cancer cells. Brn-3b also regulates target genes that can alter cell motility and drug resistance, e.g.…”

Section: Introductionmentioning

confidence: 99%

Hsp-27 induction requires POU4F2/Brn-3b TF in doxorubicin-treated breast cancer cells, whereas phosphorylation alters its cellular localisation following drug treatment

Fujita

Ounzain

Wang

et al. 2011

Cell Stress and Chaperones

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POU4F2/Brn-3b transcription factor (referred to as Brn-3b) is elevated in >60% of breast cancers and profoundly alters growth and behaviour of cancer cells by regulating distinct subsets of target genes. Previous studies showed that Brn-3b was required to maximally transactivate small heat shock protein, HSPB1/Hsp-27 (referred to as , and consequently, Brn-3b expression correlated well with Hsp27 levels in human breast biopsies. In these studies, we showed that Brn-3b is increased in MCF7 breast cancer cells that survive following treatment with chemotherapeutic drug doxorubicin (Dox) with concomitant increases in Hsp-27 expression. Targeting of Brn3b using short interfering RNA reduced Hsp-27 in Doxtreated cells, suggesting that Brn-3b regulates Hsp-27 expression under these conditions. Wound healing assays showed increased Brn-3b in Dox-treated migratory cells that also express Hsp-27. Interestingly, Hsp-27 phosphorylation and cellular localisation are also significantly altered at different times following Dox treatment. Thus, phosphoHsp-27 (p-Hsp27) protein displayed widespread distribution after 24 hrs of Dox treatment but was restricted to the nucleus after 5 days. However, in drug-resistant cells (grown in Dox for >1 month), p-Hsp-27 was excluded from nuclei and most of the cytoplasm and appeared to be associated with the cell membrane. Studies to determine how this protein promotes survival and migration in breast cancer cells showed that the protective effects were conferred by unphosphorylated Hsp-27 protein.

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“…As we did not investigate for the presence of p53 gene abnormalities, the mechanism that is responsible for the increase in the malignant potential of IDCs according to grades of lymph vessel tumor embolus from the standpoint of p53 gene abnormalities in lymph vessel tumor emboli, as well as in tumorstromal fibroblasts, or in stroma-invasive tumor cells should be investigated. In addition, as some studies have reported some identifying genes that closely regulate the cell cycle of tumors, [24][25][26] such genes should be investigated to determine whether they are candidates for p53 in regulating tumor cell cycle of lymph vessel tumor emboli.…”

Section: Discussionmentioning

confidence: 99%

Grading system for lymph vessel tumor emboli: significant outcome predictor for patients with invasive ductal carcinoma of the breast who received neoadjuvant therapy

Hasebe¹,

Tamura

Iwasaki³

et al. 2010

Modern Pathology

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The purpose of this study was to confirm that the grades of lymph vessel tumor emboli in biopsy specimens obtained before neoadjuvant therapy and in the surgical specimens obtained after neoadjuvant therapy according to the grading system we devised are significant histological outcome predictor for invasive ductal carcinoma (IDC) patients who received neoadjuvant therapy. The subjects of this study were the 318 consecutive IDC patients who had received neoadjuvant therapy in our institution. The lymph vessel tumor embolus grades in the biopsy specimens and in the surgical specimens were significantly associated with the increases in mean number of nodal metastases. Multivariate analyses with well-known prognostic factors and p53 expression in tumor-stromal fibroblasts clearly showed that the lymph vessel tumor embolus grade based on the biopsy specimens and based on the surgical specimens significantly increased the hazard rates for tumor recurrence and tumor-related death in all the IDC patients as a whole, in the IDC patients who did not have nodal metastasis, and in the IDC patients who had nodal metastasis, and the outcome-predictive power of the lymph vessel tumor embolus grades based on the surgical specimens was superior to that of the lymph vessel tumor embolus grades based on the biopsy specimens. The grades in the grading system for lymph vessel tumor emboli were significantly associated with nodal metastasis, and the histological grading system is an excellent system for accurately predicting the outcome of patients with IDC of the breast who have received neoadjuvant therapy.

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Proliferation-associated Brn-3b transcription factor can activate cyclin D1 expression in neuroblastoma and breast cancer cells

Cited by 21 publications

References 38 publications

Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma

Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma

Hsp-27 induction requires POU4F2/Brn-3b TF in doxorubicin-treated breast cancer cells, whereas phosphorylation alters its cellular localisation following drug treatment

Grading system for lymph vessel tumor emboli: significant outcome predictor for patients with invasive ductal carcinoma of the breast who received neoadjuvant therapy

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