WNT5A as a therapeutic target in breast cancer

Prasad, Chandra Prakash; Manchanda, Mansi; Mohapatra, Purusottam; Andersson, Tommy

doi:10.1007/s10555-018-9760-y

Cited by 55 publications

(38 citation statements)

References 56 publications

(78 reference statements)

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“…9,10 In fact, our more recent studies demonstrate that nuclear accumulation of β-catenin gradually augments from mild through moderate and severe dysplasia, and that these changes are associated with augmented Wnt3a in tissue biopsies. 12 Aside the requirement of Wnt ligands for nuclear accumulation of β-catenin in malignancy, 39,40 no information is available regarding molecular mechanisms involved in aberrant stabilization of β-catenin in premalignant lesions. Based on early evidence showing that endosomal sequestration of the destruction complex leads to stabilization and subsequent re-localization of β-catenin, 13,14,16,41 an intriguing possibility is that this process is upregulated in initial steps of carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Nuclear accumulation of β‐catenin is associated with endosomal sequestration of the destruction complex and increased activation of Rab5 in oral dysplasia

et al. 2020

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Potentially malignant lesions, commonly referred to as dysplasia, are associated with malignant transformation by mechanisms that remain unclear. We recently reported that increased Wnt secretion promotes the nuclear accumulation of β‐catenin and expression of target genes in oral dysplasia. However, the mechanisms accounting for nuclear re‐localization of β‐catenin in oral dysplasia remain unclear. In this study, we show that endosomal sequestration of the β‐catenin destruction complex allows nuclear accumulation of β‐catenin in oral dysplasia, and that these events depended on the endocytic protein Rab5. Tissue immunofluorescence analysis showed aberrant accumulation of enlarged early endosomes in oral dysplasia biopsies, when compared with healthy oral mucosa. These observations were confirmed in cell culture models, by comparing dysplastic oral keratinocytes (DOK) and non‐dysplastic oral keratinocytes (OKF6). Intriguingly, DOK depicted higher levels of active Rab5, a critical regulator of early endosomes, when compared with OKF6. Increased Rab5 activity in DOK was necessary for nuclear localization of β‐catenin and Tcf/Lef‐dependent transcription, as shown by expression of dominant negative and constitutively active mutants of Rab5, along with immunofluorescence, subcellular fractionation, transcription, and protease protection assays. Mechanistically, elevated Rab5 activity in DOK accounted for endosomal sequestration of components of the destruction complex, including GSK3β, Axin, and adenomatous polyposis coli (APC), as observed in Rab5 dominant negative experiments. In agreement with these in vitro observations, tissue immunofluorescence analysis showed increased co‐localization of GSK3β, APC, and Axin, with early endosome antigen 1‐ and Rab5‐positive early endosomes in clinical samples of oral dysplasia. Collectively, these data indicate that increased Rab5 activity and endosomal sequestration of the β‐catenin destruction complex leads to stabilization and nuclear accumulation of β‐catenin in oral dysplasia.

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Section: Discussionmentioning

confidence: 99%

Nuclear accumulation of β‐catenin is associated with endosomal sequestration of the destruction complex and increased activation of Rab5 in oral dysplasia

et al. 2020

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“…Some members of the Wnt family, such as WNT5A, act as an antagonist of canonical Wnt signaling in some cancers such as colon cancer [166] breast cancer [167] and leukemia [168]. Therefore, using a small WNT5A-mimicking peptide Foxy5 has been suggested as a future anti-metastatic treatment strategy for breast cancer patients [169]. The drug is under phase II clinical investigation to treat colon cancer.…”

Section: Wnt/β-catenin Inhibitorsmentioning

confidence: 99%

Transcription Factors in Cancer Development and Therapy

Vishnoi

Viswakarma

Rana

et al. 2020

Cancers

103

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Cancer is a multi-step process and requires constitutive expression/activation of transcription factors (TFs) for growth and survival. Many of the TFs reported so far are critical for carcinogenesis. These include pro-inflammatory TFs, hypoxia-inducible factors (HIFs), cell proliferation and epithelial–mesenchymal transition (EMT)-controlling TFs, pluripotency TFs upregulated in cancer stem-like cells, and the nuclear receptors (NRs). Some of those, including HIFs, Myc, ETS-1, and β-catenin, are multifunctional and may regulate multiple other TFs involved in various pro-oncogenic events, including proliferation, survival, metabolism, invasion, and metastasis. High expression of some TFs is also correlated with poor prognosis and chemoresistance, constituting a significant challenge in cancer treatment. Considering the pivotal role of TFs in cancer, there is an urgent need to develop strategies targeting them. Targeting TFs, in combination with other chemotherapeutics, could emerge as a better strategy to target cancer. So far, targeting NRs have shown promising results in improving survival. In this review, we provide a comprehensive overview of the TFs that play a central role in cancer progression, which could be potential therapeutic candidates for developing specific inhibitors. Here, we also discuss the efforts made to target some of those TFs, including NRs.

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“…is reportedly involved in the progression of cancer [16,34,35] . In this study, we identi ed WNT5A exerts tumor-suppressive functions, inhibiting the growth and aggressiveness of EGFR-mutant NSCLC cells, via in uencing the activity of β-catenin and downregulating the downstream gene expression, including CCND1, CD44 and ZEB1.…”

Section: Discussionmentioning

confidence: 99%

E2F1-mediated repression of WNT5A expression promotes brain metastasis dependent on the ERK1/2 pathway in EGFR-mutant non-small cell lung cancer

Tong

Meng

et al. 2020

Cell. Mol. Life Sci.

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Background: Brain metastasis (BM) is associated with poor prognosis in patients with advanced nonsmall cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutation reportedly enhances the development of BM. However, the exact mechanism of how EGFR-mutant NSCLC contributes to BM remains unknown. This study was aimed at exploring the mechanism of BM development in EGFRmutant NSCLC. Methods: WNT5A, was identi ed by analyzing RNA sequencing data of BM tissue from NSCLC. The expression of WNT5A in NSCLC plasma (n=94) and cells were detected by quantitative real-time PCR (qRT-PCR) and western blotting. WNT5A functions were examined by cell viability, migration, invasion, and immunohistochemistry assay in vitro. A xenograft nude mouse model and BM model were used to observe tumor growth and brain metastasis in vivo. The potential transcription factor of WNT5A was explored using bioinformatics analysis and veri ed by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. WNT5A targets in NSCLC cells were con rmed using luciferase reporter assay, qRT-PCR, and western blotting. Results: WNT5A was downregulated in BM tissues and EGFR-mutant samples and cells. The overexpression of WNT5A inhibited the growth, migration, and invasion of EGFR-mutant cells in vitro and retarded tumor growth and metastasis in vivo compared to the EGFR wide-type cells. ChIP and luciferase reporter assays showed that E2F1 negatively regulated WNT5A at transcriptional levels, which was suppressed by ERK1/2 inhibitor (U0126) in EGFR-mutant cells. Furthermore, WNT5A inhibited β-catenin activity and the transcriptional levels of its downstream genes in cancer progression. Conclusions: Our research revealed the role of WNT5A in NSCLC BM with EGFR mutation and proved that E2F1-mediated repression of WNT5A was dependent on the ERK1/2 pathway, supporting the notion that targeting the ERK1/2-E2F1-WNT5A pathway could be an effective strategy for treating BM in EGFRmutant NSCLC. PI3K/AKT or extracellular signal-regulated kinase 1/2 (ERK1/2) pathway [6,7]. Emerging evidence suggests that EGFR-mutant advanced NSCLC is particularly prone to develop the BM, implying that EGFR mutation could be a risk factor for BM in NSCLC [5,8]. However, the exact mechanism of how EGFR mutation in lung cancer contributes to brain metastasis remains largely unknown. Unlike canonical Wnt/β-catenin signaling, WNT5A, as a member of non-canonical Wnt signaling, controls various aspects of cell migration, which are essential in normal and malignant development [9,10] and the aberrant expression of WNT5A induces distinct effects in different types of cancer [10-16]. Previous studies have shown that WNT5A has two protein isoforms, namely WNT5A-long and WNT5A-short; the former inhibits the proliferation of tumor cell lines, while the latter promotes their growth [17]. In addition, WNT5A has a vital role in neuron development in association with the EGFR pathway [18]. However, the underlying mechanism for this correlation in BM with lung cancer has not yet bee...

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WNT5A as a therapeutic target in breast cancer

Cited by 55 publications

References 56 publications

Nuclear accumulation of β‐catenin is associated with endosomal sequestration of the destruction complex and increased activation of Rab5 in oral dysplasia

Nuclear accumulation of β‐catenin is associated with endosomal sequestration of the destruction complex and increased activation of Rab5 in oral dysplasia

Transcription Factors in Cancer Development and Therapy

E2F1-mediated repression of WNT5A expression promotes brain metastasis dependent on the ERK1/2 pathway in EGFR-mutant non-small cell lung cancer

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