XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype

Evans, Myron K.; Brown, Michael C.; Geradts, Joseph; Bao, Xiaoyong; Robinson, Timothy J.; Jolly, Mohit Kumar; Vermeulen, Peter; Palmer, Gregory M.; Gromeier, Matthias; Levine, Herbert; Morse, Michael A.; Laere, Steven J. Van; Devi, Gayathri R.

doi:10.1158/0008-5472.can-17-1667

Cited by 46 publications

(33 citation statements)

References 53 publications

(58 reference statements)

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“…The present study determined that in patients with TNBC, both MAPK and EGFR expression were significantly associated with both lymph node metastasis and clinical stage. It has also been discovered that patients with high levels of MAPK and EGFR expression are more prone to early recurrence, metastasis and poor prognosis (23)(24)(25). However, two studies elucidated that there was no significant correlation between MAPK expression and lymph node metastasis (6,20), which was not consistent with the results of the present study.…”

Section: Discussioncontrasting

confidence: 96%

Expression and clinical significance of MAPK and EGFR in triple‑negative breast cancer

et al. 2020

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To investigate the expression and clinical significance of mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) in triple-negative breast cancer (TNBC), a total of 300 TNBC and 120 paired paracancerous tissues were examined. Immunohistochemistry was conducted to determine the expression levels of MAPK and EGFR, and the correlation between MAPK and EGFR expression was evaluated using Cramer's V test. The association between MAPK and EGFR expression, and various clinicopathological variables (such as lymph node metastasis, clinical stage, recurrence and metastasis) was also evaluated, using the χ 2 test. MAPK and EGFR expression levels in TNBC tissues were significantly higher than in the paired paracancerous tissues. Moreover, MAPK expression was associated with that of EGFR in TNBC tissues. The positive expression rates of MAPK and EGFR in patients with lymph node metastasis, advanced clinical stage, tumor recurrence and metastasis were higher than those without. Patients with positive expression of MAPK and EGFR in TNBC tissues had poorer prognoses and lower overall survival times than those without expression. In summary, the expression of MAPK and EGFR is closely associated with tumor invasion and the metastasis of TNBC, and may therefore be used as an indicator of poor prognosis in patients with TNBC.

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Section: Discussioncontrasting

confidence: 96%

Expression and clinical significance of MAPK and EGFR in triple‑negative breast cancer

et al. 2020

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“…Second, IBC patients have significantly higher levels of IL-6 levels in serum and carcinoma tissues compared with non-IBC ones (73). Third, CD24 hi CD44 hi and ALDH+ cells that represent a hybrid E/M phenotype (20) and form aggressive tumors in vivo (74,75) are enriched in IBC upon drug treatment (15) and exhibit up-regulated Notch-Jagged signaling (5). Fourth, Notch-JAG1 signaling mediates resistance to tamoxifen (44) and is enriched upon inhibition of HER2 (42), suggesting how adaptive resistance mediated by JAG1 can contribute to tumor relapse.…”

Section: Discussionmentioning

confidence: 99%

Toward understanding cancer stem cell heterogeneity in the tumor microenvironment

Bocci

Gearhart-Serna

Boareto

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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263

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The epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) formation are two paramount processes driving tumor progression, therapy resistance, and cancer metastasis. Recent experiments show that cells with varying EMT and CSC phenotypes are spatially segregated in the primary tumor. The underlying mechanisms generating such spatiotemporal dynamics in the tumor microenvironment, however, remain largely unexplored. Here, we show through a mechanism-based dynamical model that the diffusion of EMT-inducing signals such as TGF-β, together with noncell autonomous control of EMT and CSC decision making via the Notch signaling pathway, can explain experimentally observed disparate localization of subsets of CSCs with varying EMT phenotypes in the tumor. Our simulations show that the more mesenchymal CSCs lie at the invasive edge, while the hybrid epithelial/mesenchymal (E/M) CSCs reside in the tumor interior. Further, motivated by the role of Notch-Jagged signaling in mediating EMT and stemness, we investigated the microenvironmental factors that promote Notch-Jagged signaling. We show that many inflammatory cytokines such as IL-6 that can promote Notch-Jagged signaling can (i) stabilize a hybrid E/M phenotype, (ii) increase the likelihood of spatial proximity of hybrid E/M cells, and (iii) expand the fraction of CSCs. To validate the predicted connection between Notch-Jagged signaling and stemness, we knocked down JAG1 in hybrid E/M SUM149 human breast cancer cells in vitro. JAG1 knockdown significantly restricted tumor organoid formation, confirming the key role that Notch-Jagged signaling can play in tumor progression. Together, our integrated computational–experimental framework reveals the underlying principles of spatiotemporal dynamics of EMT and CSCs.

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“…There is a controversy among researchers about the origin of BCSCs, in which normal stem cells, progenitor cells, or differentiated cells can be considered as an origin of BCSCs (11). Deregulation of signaling pathways including mitogen-activated protein (MAP) kinase, PI3K/Akt/nuclear factor kappa B (NFκB), TGF-β, hedgehog (Hh), Notch, Wnt/β-catenin, and Hippo pathway in normal stem cells, progenitor cells, or differentiated cells may transform them to CSCs due to genetic and epigenetic changes (12)(13)(14). In addition, the expression of the specific molecules in these signaling pathways can be deregulated in BCSCs as well as microRNAs (miRNAs).…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Pathways of Malignancy in Breast Cancer Stem Cells

Yousefnia

Forootan

et al. 2020

Front. Oncol.

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Breast cancer stem cells (BCSCs) are the minor population of breast cancer (BC) cells that exhibit several phenotypes such as migration, invasion, self-renewal, and chemotherapy as well as radiotherapy resistance. Recently, BCSCs have been more considerable due to their capacity for recurrence of tumors after treatment. Recognition of signaling pathways and molecular mechanisms involved in stemness phenotypes of BCSCs could be effective for discovering novel treatment strategies to target BCSCs. This review introduces BCSC markers, their roles in stemness phenotypes, and the dysregulated signaling pathways involved in BCSCs such as mitogen-activated protein (MAP) kinase, PI3K/Akt/nuclear factor kappa B (NFκB), TGF-β, hedgehog (Hh), Notch, Wnt/β-catenin, and Hippo pathway. In addition, this review presents recently discovered molecular mechanisms implicated in chemotherapy and radiotherapy resistance, migration, metastasis, and angiogenesis of BCSCs. Finally, we reviewed the role of microRNAs (miRNAs) in BCSCs as well as several other therapeutic strategies such as herbal medicine, biological agents, anti-inflammatory drugs, monoclonal antibodies, nanoparticles, and microRNAs, which have been more considerable in the last decades.

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XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype

Cited by 46 publications

References 53 publications

Expression and clinical significance of MAPK and EGFR in triple‑negative breast cancer

Expression and clinical significance of MAPK and EGFR in triple‑negative breast cancer

Toward understanding cancer stem cell heterogeneity in the tumor microenvironment

Mechanistic Pathways of Malignancy in Breast Cancer Stem Cells

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