Roles and regulation of Wnt signaling and β-catenin in prostate cancer

Verras, Meletios; Sun, Zijie

doi:10.1016/j.canlet.2005.06.004

Cited by 164 publications

(167 citation statements)

References 83 publications

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“…9,11,12 Evidence supports the presence of cancer Figure 8 Gene expression in ovarian cancer patient samples. (a) RSPO3 expression before treatment with carboplatin and WNT974 or carboplatin only is compared with the response in ascites cells after treatment.…”

Section: Discussionmentioning

confidence: 98%

“…The Wnt/ β-catenin pathway is a signaling pathway that mediates ovarian cancer initiation and progression through genes that regulate cell proliferation and apoptosis. [11][12][13] Preclinical studies have shown an upregulation of Wnt ligands in ovarian cancer ascites, which suggests an increase in Wnt/β-catenin pathway activity. 9 The Wnt/β-catenin pathway has also been shown to contribute to chemoresistance in ovarian cancer as it promotes epithelial-to-mesenchymal transition.…”

mentioning

confidence: 99%

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Targeting the Wnt/β-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974

Boone

Arend

Johnston

et al. 2016

Laboratory Investigation

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Preclinical studies in ovarian cancer have demonstrated upregulation of the Wnt/β-catenin pathway promoting tumor proliferation and chemoresistance. Our objective was to evaluate the effect of the Wnt/β-catenin pathway inhibitor, WNT974, in primary ovarian cancer ascites cells. Ascites cells from patients with papillary serous ovarian cancer were isolated and treated with 1 μM WNT974 ± 100 μM carboplatin. Viability was evaluated with the ATPlite assay. The IC 50 was calculated using a dose-response analysis. Immunohistochemistry (IHC) was performed on ascites cells and tumor. Expression of R-spondin 2 (RSPO2), RSPO3, PORCN, WLS, AXIN2, and three previously characterized RSPO fusion transcripts were assessed using Taqman assays. Sixty ascites samples were analyzed for response to WNT974. The ascites samples that showed a decrease in ATP concentration after treatment demonstrated no difference from the untreated cells in percent viability with trypan blue staining. Flow cytometry demonstrated fewer cells in the G2 phase and more in the G1 and S phases after treatment with WNT974. Combination therapy with WNT974 and carboplatin resulted in a higher percentage of samples that showed ≥ 30% reduction in ATP concentration than either single drug treatment. IHC analysis of Wnt pathway proteins suggests cell cycle arrest rather than cytotoxicity after WNT974 treatment. QPCR indicated that RSPO fusions are not prevalent in ovarian cancer tissues or ascites. However, higher PORCN expression correlated to sensitivity to WNT974 (P = 0.0073). In conclusion, WNT974 produces cytostatic effects in patient ascites cells with primary ovarian cancer through inhibition of the Wnt/β-catenin pathway. The combination of WNT974 and carboplatin induces cytotoxicity plus cell cycle arrest in a higher percentage of ascites samples than with single drug treatment. RSPO fusions do not contribute to WNT974 sensitivity; however, higher PORCN expression indicates increased WNT974 sensitivity.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Targeting the Wnt/β-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974

Boone

Arend

Johnston

et al. 2016

Laboratory Investigation

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“…The identification of b-catenin, as an AR cofactor, substantiated a possible role of Wnt signaling in prostate cancer development and progression. 4,10 Several lines of evidence have shown that b-catenin can co-localize with AR in the nucleus and enhance AR-mediated transcription through a proteinprotein interaction. 4 Another study has confirmed this result where enhanced androgen-mediated transcription with the overexpression of b-catenin was identified in prostate cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…The biological significance of b-catenin in prostate cancer cells is actually exposed by the discovery of a proteinprotein interaction between AR and b-catenin. 4 Through this interaction, b-catenin not only selectively binds to AR, but also augments the ligand-dependent activity of AR in LNCaP cells. 5,6 Androgens were shown to enhance the b-catenin to AR interaction, and the ligand-binding domain of AR was mapped to be responsible for this binding.…”

Section: Introductionmentioning

confidence: 99%

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Curcumin interrupts the interaction between the androgen receptor and Wnt/β-catenin signaling pathway in LNCaP prostate cancer cells

Choi

Lim

Hong

2010

Prostate Cancer Prostatic Dis

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Recently, studies have investigated the significance of the Wnt/b-catenin pathway in prostate cancer. The transcriptional activity of the androgen receptor (AR) is modulated by interaction with coregulators, one of which is b-catenin. Curcumin, a dietary yellow pigment of Curcuma longa, has emerged as having a chemopreventive role. Although curcumin has been shown to inhibit AR expression, its molecular mechanism has not been fully elucidated. In this study, whether curcumin mediates the Wnt/b-catenin signaling pathway with regard to AR/b-catenin interactions was studied. Curcumin was shown to induce significant inhibition of AR expression in a dose-dependent manner. Marked curcumin-induced suppression of b-catenin was shown in the nuclear and cytoplasmic extracts as well as whole cell lysates. Further analysis revealed that phosphorylation of Akt and glycogen synthase kinase-3b were attenuated, but phosphorylated b-catenin was increased after curcumin treatment. Finally, cyclin D1 and c-myc, the target gene of the b-catenin/T-cell factor transcriptional complex, were also decreased. These findings suggest that curcumin modulates the Wnt/b-catenin signaling pathway and might have a significant role in mediating inhibitory effects on LNCaP prostate cancer cells.

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Quantitative HER2 protein levels predict outcome in fluorescence in situ hybridization‐positive patients with metastatic breast cancer treated with trastuzumab

Lipton

Köstler

Leitzel

et al. 2010

Cancer

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BACKGROUND: Only a portion of breast cancer patients currently selected for trastuzumab therapy respond. METHODS: Using a novel assay (HERmark) to quantify total human epidermal growth factor receptor 2 (HER2) expression, the authors examined outcomes in 102 trastuzumab-treated metastatic breast cancer patients previously assessed as immunohistochemistry (IHC) 3þ by local but not central IHC, or fluorescence in situ hybridization (FISH) positive, and then retested by central FISH. RESULTS: Of 102 MBC patients previously scored as IHC 3þ or 2þ/FISHpositive and treated with trastuzumab-containing regimens, 98 had both central FISH and HER2 total expression values. Sixty-six of 76 central FISH-positive patients (87%) had high HER2 total expression levels (concordant positive), and 19 of 22 central FISH-negative patients (86%) were HER2 total expression low (concordant negative). Fourteen percent (3 of 22) of central FISH-negative patients were HER2 total expression high (discordant HER2 total expression high), and 13% (10 of 76) of central FISH-positive patients were HER2 total expression low (discordant HER2 total expression low). The concordant positive group had a significantly longer time to progression (TTP, median ¼ 11.3 months) compared with the concordant negative group (median TTP, 4.5 months; hazard ratio [HR] ¼ 0.42, P < .001), and also compared with the discordant HER2 total expression low group (median TTP, 3.7 months; HR ¼ 0.43, P ¼ .01). The discordant HER2 total expression low group behaved similarly compared with concordant negatives (HR ¼ 1, P ¼ .99). In analyses restricted to central FISH-positive patients only (n ¼ 77), Cox proportional hazards multivariate regression identified HER2 total expression as an independent predictor of TTP (HR ¼ 0.29, P ¼ .0015) and overall survival (HR ¼ 0.19, P < .001). CONCLUSIONS: A subset of patients with HER2 gene amplification by FISH express low levels of HER2 protein and have reduced response to trastuzumab-containing therapy, similar to FISH-negative

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Roles and regulation of Wnt signaling and β-catenin in prostate cancer

Cited by 164 publications

References 83 publications

Targeting the Wnt/β-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974

Targeting the Wnt/β-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974

Curcumin interrupts the interaction between the androgen receptor and Wnt/β-catenin signaling pathway in LNCaP prostate cancer cells

Quantitative HER2 protein levels predict outcome in fluorescence in situ hybridization‐positive patients with metastatic breast cancer treated with trastuzumab

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