β-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis

Klemm, Florian; Bleckmann, Annalen; Siam, Laila; Chuang, Han-Ning; Rietkötter, Eva; Behme, Daniel; Schulz, Matthias; Schaffrinski, Meike; Schindler, Sabrina; Trümper, Lorenz; Krämer, Frank; Beißbarth, Tim; Stadelmann, Christine; Binder, Claudia R.; Pukrop, Tobias

doi:10.1093/carcin/bgq269

Cited by 123 publications

(132 citation statements)

References 56 publications

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“…S8A and S8B), the EGFR-phosphatidylinositide 3-kinase (PI3K)-AKT-mTOR-MAPK pathway, and the TGF-WNT cytoskeleton-remodeling pathway. 27 Unexpectedly, we identified a tumor necrosis factor (TNF)-IAP apoptotic pathway ( Fig. 7A and 7B), DNA damage ATM-ATR pathway (Suppl.…”

Section: Meta-analysis Of Common Pathways Among Platformsmentioning

confidence: 87%

Causal Network Models for Predicting Compound Targets and Driving Pathways in Cancer

et al. 2014

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Gene-expression data are often used to infer pathways regulating transcriptional responses. For example, differentially expressed genes (DEGs) induced by compound treatment can help characterize hits from phenotypic screens, either by correlation with known drug signatures or by pathway enrichment. Pathway enrichment is, however, typically computed with DEGs rather than "upstream" nodes that are potentially causal of "downstream" changes. Here, we present graphbased models to predict causal targets from compound-microarray data. We test several approaches to traversing network topology, and show that a consensus minimum-rank score (SigNet) beat individual methods and could highly rank compound targets among all network nodes. In addition, larger, less canonical networks outperformed linear canonical interactions. Importantly, pathway enrichment using causal nodes rather than DEGs recovers relevant pathways more often. To further validate our approach, we used integrated data sets from the Cancer Genome Atlas to identify driving pathways in triple-negative breast cancer. Critical pathways were uncovered, including the epidermal growth factor receptor 2-phosphatidylinositide 3-kinase-AKT-MAPK growth pathway and ATR-p53-BRCA DNA damage pathway, in addition to unexpected pathways, such as TGF-WNT cytoskeleton remodeling, IL12-induced interferon gamma production, and TNFR-IAP (inhibitor of apoptosis) apoptosis; the latter was validated by pooled small hairpin RNA profiling in cancer cells. Overall, our approach can bridge transcriptional profiles to compound targets and driving pathways in cancer.

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Section: Meta-analysis Of Common Pathways Among Platformsmentioning

confidence: 87%

Causal Network Models for Predicting Compound Targets and Driving Pathways in Cancer

et al. 2014

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“…A role for Wnt signaling in primary breast cancers of the ER-negative subtype has been described [19, 41]. A phase II clinical trial of bicalutamide in AR+/ER- metastatic breast cancer reported a 19% clinical benefit rate and a median increase of 12 weeks in progression-free survival [3].…”

Section: Discussionmentioning

confidence: 99%

Androgen Receptor Expression and Bicalutamide Antagonize Androgen Receptor Inhibit β-Catenin Transcription Complex in Estrogen Receptor-Negative Breast Cancer

Huang

Han

Liang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Little is known about the potential mechanism of action for androgen receptor (AR) targeting treatment in estrogen receptor (ER)-negative breast cancer. This study aimed to evaluate AR status and its prognosis in four breast cancer subtypes. Bicalutamide has been identified as an AR antagonist and used for treating AR+/ER- breast cancer in a phase II trial. Our studies will clarify its mechanism in breast cancer treatment. Methods: A total of 510 consecutive cases of invasive ductal cancer (IDC) were evaluated in this study. The expression of AR was analyzed by immunohistochemistry and compared with patient survival, and its implications were evaluated in four subtypes of IDC. We examined bicalutamide as an AR antagonist to inhibit proliferation and increased apoptosis in AR+/ER- breast cancer cell lines. We explored the tumor suppressive functions of bicalutamide in vitro and vivo and its related mechanisms in AR+/ER- breast cancer. Results: AR expression was related to that of ER (P<0.001), PR (P<0.001), Her2 (P=0.017), Ki-67(P=0.020) and to four subtypes (P<0.001). AR retained independent prognostic signifcance (P=0.007, ER- cases; P=0.001, ER+ cases; P=0.001, total cases). We found that bicalutamide significantly decreased viability and increased apoptosis in vitro and vivo. The mechanistic analysis revealed that bicalutamide blocked androgen-stimulated oncogenic AR and Wnt/β-catenin signaling and inhibited the growth of AR+/ER- breast cancer. Conclusion: Our studies provide novel insights into bicalutamide as an antagonist of AR function in AR+/ER- breast cancer and reveal the mechanistic basis for targeting AR as a therapeutic opportunity for patients with AR+/ER- breast cancer.

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“…This triple negative tumor subtype is mainly correlated to poor outcomes, showing the worst overall and disease-free survival rates due to its metastatic and invasive features. MDA-MB-231 cells exhibited invasive/metastatic tumor features with rapid migratory ability and relatively high endogenous expression of TGF-β and Wnt5a (30). In contrast to MDA-MB-231 cells, MCF-7 cells are non-invasive ER-positive breast cancer cells, representing the ER/PR positive luminal subtype.…”

Section: Introductionmentioning

confidence: 99%

Mineral-enriched deep-sea water inhibits the metastatic potential of human breast cancer cell lines

Kim

Chun

Lee

et al. 2013

International Journal of Oncology

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Abstract. Recently, the scientific community has begun to establish the health benefits of deep-sea water (DSW) due to its enrichment in nutrients and minerals. In this study, we investigated the effects of deep-sea water (DSW) on the metastatic potential of two human breast cancer cell lines exhibiting highly different phenotypes. MDA-MB-231 cells exhibit invasive/metastatic tumor features with rapid migration ability and high endogenous expression of TGF-β and Wnt5a. DSW treatment significantly inhibits their migratory ability in a wound-healing assay. This inhibitory effect of DSW appears to be mediated through TGF-β and Wnt5a signaling, resulting in attenuated expression of CD44. We further investigated the preventive effect of DSW on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced invasive/metastatic tumor features in non-invasive MCF-7 cells. Similar to the inhibitory effects shown in MDA-MB-231 cells, we observed that DSW treatment resulted in the inhibition of TPA-induced migration and MMP-9 activity with a concomitant decrease in mRNA levels of MMP-9, TGF-β, Wnt5a and Wnt3a. Taken together, our data show that DSW has inhibitory effects on breast cancer invasion/metastasis, suggesting that DSW has some promise in improving cancer survival by preventing tumor metastasis.

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β-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis

Cited by 123 publications

References 56 publications

Causal Network Models for Predicting Compound Targets and Driving Pathways in Cancer

Causal Network Models for Predicting Compound Targets and Driving Pathways in Cancer

Androgen Receptor Expression and Bicalutamide Antagonize Androgen Receptor Inhibit β-Catenin Transcription Complex in Estrogen Receptor-Negative Breast Cancer

Mineral-enriched deep-sea water inhibits the metastatic potential of human breast cancer cell lines

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