HOXC11–SRC-1 regulation of S100beta in cutaneous melanoma: new targets for the kinase inhibitor dasatinib

deBlacam, C; Byrne, Christopher; Hughes, Éamon; McIlroy, Marie; Bane, Fiona T.; Hill, Arnold D.; Young, Leonie S.

doi:10.1038/bjc.2011.193

Cited by 19 publications

(15 citation statements)

References 20 publications

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“…These results clearly identified CSF1 as a direct novel target gene of NCOA1 and c-Jun/c-Fos in BrCa cells. Recent studies have also demonstrated that NCOA1 serves as a coactivator for PEA3, c-Jun/c-Fos, Ets-2 and HOXC11 to upregulate Twist1 , integrin α 5 ( ITGA5 ), c-Myc and S100β expression, respectively, which in turn promotes BrCa cell EMT, migration, invasion and/or resistance to endocrine therapies (18, 19, 46, 47). Together, these findings indicate that NCOA1 can coactivate different TFs to regulate multiple target genes important for BrCa.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, targeting NCOA1 could inhibit CSF1 expression and CSF1 expression-induced BrCa cell invasion and metastasis. Given that NCOA1 also upregulates other genes important for BrCa cell survival, invasion and metastasis, such as Twist1 , ITGA5 , c-Myc and S100β (18, 19, 46, 47), NCOA1 may be a potential molecular target for inhibiting BrCa progression and metastasis.…”

Section: Discussionmentioning

confidence: 99%

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NCOA1 Directly Targets M-CSF1 Expression to Promote Breast Cancer Metastasis

Qin

Toneff

et al. 2014

Cancer Research

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In breast cancer (BrCa), overexpression of the nuclear co-activator NCOA1 (SRC-1) is associated with disease recurrence and resistance to endocrine therapy. To examine the impact of NCOA1 overexpression on morphogenesis and carcinogenesis in the mammary gland (MG), we generated MMTV-hNCOA1 transgenic [Tg(NCOA1)] mice. In the context of two distinct transgenic models of breast cancer, NCOA1 overexpression did not affect the morphology or tumor forming capability of MG epithelial cells. However, NCOA1 overexpression increased the number of circulating BrCa cells and the efficiency of lung metastasis. Mechanistic investigations showed that NCOA1 and c-Fos were recruited to a functional AP-1 site in the macrophage attractant CSF1 promoter, directly upregulating CSF1 expression to enhance macrophage recruitment and metastasis. Conversely, silencing NCOA1 reduced CSF1 expression and decreased macrophage recruitment and BrCa cell metastasis. In a cohort of 453 human breast tumors, NCOA1 and CSF1 levels correlated positively with disease recurrence, higher tumor grade and poor prognosis. Together, our results define an NCOA1/AP-1/CSF1 regulatory axis that promotes BrCa metastasis, offering a novel therapeutic target for impeding this process.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NCOA1 Directly Targets M-CSF1 Expression to Promote Breast Cancer Metastasis

Qin

Toneff

et al. 2014

Cancer Research

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“…Thus, treatment with the Src/Abl inhibitor, dasatinib, reduced the HOXC11-SRC-1 interaction and prevented recruitment of HOXC11 to the S100B promoter, so the mRNA and protein levels for S100B were both reduced, as was the growth and migratory properties of drug-treated MeWo melanoma cells. Thus, profiling patients for HOXC11 and S100B levels has the potential to increase the efficacy of dasatinib treatment in melanoma [415]. It is also noteworthy that the effect of specific drugs can be tissue-specific, particularly for regulation of the S100A2 gene, which is thought to suppress growth in some cell types (i.e.…”

Section: Therapeutic Considerations For the S100 Protein Familymentioning

confidence: 99%

Functions of S100 Proteins

Donato¹,

Cannon²,

Sorci³

et al. 2013

Current Molecular Medicine

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The S100 protein family consists of 24 members functionally distributed into three main subgroups: those that only exert intracellular regulatory effects, those with intracellular and extracellular functions and those which mainly exert extracellular regulatory effects. S100 proteins are only expressed in vertebrates and show cell-specific expression patterns. In some instances, a particular S100 protein can be induced in pathological circumstances in a cell type that does not express it in normal physiological conditions. Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion through interactions with a variety of target proteins including enzymes, cytoskeletal subunits, receptors, transcription factors and nucleic acids. Some S100 proteins are secreted or released and regulate cell functions in an autocrine and paracrine manner via activation of surface receptors (e.g. the receptor for advanced glycation end-products and toll-like receptor 4), G-protein-coupled receptors, scavenger receptors, or heparan sulfate proteoglycans and N-glycans. Extracellular S100A4 and S100B also interact with epidermal growth factor and basic fibroblast growth factor, respectively, thereby enhancing the activity of the corresponding receptors. Thus, extracellular S100 proteins exert regulatory activities on monocytes/macrophages/microglia, neutrophils, lymphocytes, mast cells, articular chondrocytes, endothelial and vascular smooth muscle cells, neurons, astrocytes, Schwann cells, epithelial cells, myoblasts and cardiomyocytes, thereby participating in innate and adaptive immune responses, cell migration and chemotaxis, tissue development and repair, and leukocyte and tumor cell invasion.

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“…Dasatinib treatment also inhibited migration of SK-MEL-28 cells via decreased phosphorylation of FAK [135]. Migration of metastatic melanoma cells harvested from lymph nodes (MeWo cells) was decreased by dasatinib-mediated inhibition of homeobox C11 (HOXC11) protein interactions with Src [136]. Dasatinib treatment of uveal melanoma cells injected into zebrafish models has also demonstrated potent anti-migratory effects [137].…”

Section: Effects Of Small Molecule Inhibitors On Emt In Melanomamentioning

confidence: 99%

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

et al. 2017

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Melanoma is a cutaneous neoplastic growth of melanocytes with great potential to invade and metastasize, especially when not treated early and effectively. Epithelial-mesenchymal transition (EMT) is the process by which melanocytes lose their epithelial characteristics and acquire mesenchymal phenotypes. Mesenchymal protein expression increases the motility, invasiveness, and metastatic potential of melanoma. Many pathways play a role in promotion of mesenchymal protein expression including RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, Wnt/β-catenin, and several others. Downstream effectors of these pathways induce expression of EMT transcription factors including Snail, Slug, Twist, and Zeb that promote repression of epithelial and induction of mesenchymal character. Emerging research has demonstrated that a variety of small molecule inhibitors as well as phytochemicals can influence the progression of EMT and may even reverse the process, inducing re-expression of epithelial markers. Phytochemicals are of particular interest as supplementary treatment options because of their relatively low toxicities and anti-EMT properties. Modulation of EMT signaling pathways using synthetic small molecules and phytochemicals is a potential therapeutic strategy for reducing the aggressive progression of metastatic melanoma. In this review, we discuss the emerging pathways and transcription factor targets that regulate EMT and evaluate potential synthetic small molecules and naturally occurring compounds that may reduce metastatic melanoma progression.

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HOXC11–SRC-1 regulation of S100beta in cutaneous melanoma: new targets for the kinase inhibitor dasatinib

Cited by 19 publications

References 20 publications

NCOA1 Directly Targets M-CSF1 Expression to Promote Breast Cancer Metastasis

NCOA1 Directly Targets M-CSF1 Expression to Promote Breast Cancer Metastasis

Functions of S100 Proteins

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

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