An EGFR-ERK-SOX9 Signaling Cascade Links Urothelial Development and Regeneration to Cancer

Ling, Shizhang; Chang, Xiaofei; Schultz, Luciana; Lee, Thomas K.; Chaux, Alcides; Marchionni, Luigi; Netto, George J.; Sidransky, David; Berman, David M.

doi:10.1158/0008-5472.can-10-3072

Cited by 101 publications

(98 citation statements)

References 47 publications

(64 reference statements)

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“…Autocrine-mediated EGFR signaling has been shown to play an essential role in normal human urothelial cell proliferation and migration during wound repair in vitro (26,27). The induction of various EGFR ligands and activation of EGFR signaling in the mouse urothelium in response to local damage indicates that autocrine EGFR signaling is also involved in urothelial wound repair in vivo (15). Thus, the enrichment in expression of genes associated with wound healing and the involvement of EGFR signaling in basal-like tumors suggest that this subgroup of tumors exploits the program responsible for driving regenerative repair in normal urothelium.…”

Section: Discussionmentioning

confidence: 99%

“…The same pathway analysis performed independently on the six public MIBC series confirmed this finding (table S7). EGFR, the genes encoding five of its six ligands (AREG, AREGB, EREG, HBEGF, and TGFA), a downstream effector of EGFR (MYC), and genes known to be induced by EGFR activation in the urothelium (IL8 and SOX9) (15,16) were overexpressed in basal-like tumors. A schematic representation of these results is given in Fig.…”

Section: Egfr Pathway Is Activated In Human Basal-like Mibcmentioning

confidence: 99%

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EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype

et al. 2014

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Muscle-invasive bladder carcinoma (MIBC) constitutes a heterogeneous group of tumors with a poor outcome. Molecular stratification of MIBC may identify clinically relevant tumor subgroups and help to provide effective targeted therapies. From seven series of large-scale transcriptomic data (383 tumors), we identified an MIBC subgroup accounting for 23.5% of MIBC, associated with shorter survival and displaying a basal-like phenotype, as shown by the expression of epithelial basal cell markers. Basal-like tumors presented an activation of the epidermal growth factor receptor (EGFR) pathway linked to frequent EGFR gains and activation of an EGFR autocrine loop. We used a 40-gene expression classifier derived from human tumors to identify human bladder cancer cell lines and a chemically induced mouse model of bladder cancer corresponding to human basal-like bladder cancer. We showed, in both models, that tumor cells were sensitive to anti-EGFR therapy. Our findings provide preclinical proof of concept that anti-EGFR therapy can be used to target a subset of particularly aggressive MIBC tumors expressing basal cell markers and provide diagnostic tools for identifying these tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Egfr Pathway Is Activated In Human Basal-like Mibcmentioning

confidence: 99%

EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype

et al. 2014

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“…Indeed, it should be emphasized that additional mechanisms may drive SOX9 expression in TMPRSS2:ERG fusion-negative PCa, and may further modulate its expression in fusion-positive PCa. Interestingly, among these other mechanisms are the Wnt/β-catenin and receptor tyrosine kinase/MAP kinase pathways (24,29,47). Therefore, higher levels of SOX9 expression (above the AR-and ERG-stimulated levels in fusion-positive tumors or above the lower basal levels in fusion-negative tumors) may be a biomarker for the activation of additional pathways that can drive PCa progression through SOX9-dependent and -independent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…SOX9 mutations cause the disease campomelic dysplasia, which is characterized by extreme cartilage and bone malformation, frequent XY sex reversal, and multiple defects in other organs, consistent with an important role in tissue development (18,19). In the adult, SOX9 contributes to maintenance of stem/progenitor cells in tissues including intestine, liver, pancreas, and hair follicle (20)(21)(22)(23)(24), and dysregulated SOX9 expression has been implicated in the pathogenesis of several cancers (25)(26)(27)(28)(29)(30)(31). Similar to AR, SOX9 is required for prostate development, and accumulating evidence indicates that it contributes to the development of PCa (32)(33)(34)(35)(36)(37)(38)(39).…”

Section: Introductionmentioning

confidence: 99%

ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancer

Cai

Wang²,

He³

et al. 2013

J. Clin. Invest.

232

181

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Fusion of the androgen receptor-regulated (AR-regulated) TMPRSS2 gene with ERG in prostate cancer (PCa) causes androgen-stimulated overexpression of ERG, an ETS transcription factor, but critical downstream effectors of ERG-mediating PCa development remain to be established. Expression of the SOX9 transcription factor correlated with TMPRSS2:ERG fusion in 3 independent PCa cohorts, and ERG-dependent expression of SOX9 was confirmed by RNAi in the fusion-positive VCaP cell line. SOX9 has been shown to mediate ductal morphogenesis in fetal prostate and maintain stem/progenitor cell pools in multiple adult tissues, and has also been linked to PCa and other cancers. SOX9 overexpression resulted in neoplasia in murine prostate and stimulated tumor invasion, similarly to ERG. Moreover, SOX9 depletion in VCaP cells markedly impaired invasion and growth in vitro and in vivo, establishing SOX9 as a critical downstream effector of ERG. Finally, we found that ERG regulated SOX9 indirectly by opening a cryptic AR-regulated enhancer in the SOX9 gene.Together, these results demonstrate that ERG redirects AR to a set of genes including SOX9 that are not normally androgen stimulated, and identify SOX9 as a critical downstream effector of ERG in TMPRSS2:ERG fusion-positive PCa.

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“…SOX9 is probably the earliest epidermal SC marker, and its expression is restricted to the bulge region in adult skin (41). SOX9 is essential for the morphogenesis of both HF and SG, and its expression can be induced by EGFR signaling (48), making this transcription factor an interesting candidate as a mediator of EPGN actions on the SG. However, epidermal whole mounts of tail skin from P0 or P3 K14-EPGN mice treated with Dox from E11.5 showed no visible changes in the number or distribution of and control (Co) mice were evaluated weekly for 22 weeks with a Sebumeter (n ϭ 3 to 6 mice for each genotype).…”

Section: Sg Enlargement In K14-epgn Mice Is Associated With An Expandmentioning

confidence: 99%

Overexpression of Epigen during Embryonic Development Induces Reversible, Epidermal Growth Factor Receptor-Dependent Sebaceous Gland Hyperplasia

Dahlhoff¹,

Frances

Kloepper

et al. 2014

Molecular and Cellular Biology

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fThe epidermal growth factor receptor (EGFR) system is a key regulator of epithelial development and homeostasis. Its functions in the sebaceous gland (SG), however, remain poorly characterized. In this study, using a transgenic mouse line with tissue-specific and inducible expression of the EGFR ligand epigen, we showed that increased activation of the EGFR in skin keratinocytes results in enlarged SGs and increased sebum production. The phenotype can be reverted by interrupting transgene expression and is EGFR dependent, as gland size and sebum levels return to normal values after crossing to the EGFR-impaired mouse line Wa5. Intriguingly, however, the SG enlargement appears only if EGFR activation occurs before birth. Importantly, the enlarged sebaceous glands are associated with an increased expression of the transcription factor MYC and of the transmembrane proteins LRIG1, an established negative-feedback regulator of the EGFR/ERBB tyrosine kinase receptors and a stem cell marker. Our findings identify EGFR signaling as a major pathway determining SG activity and suggest a functional relationship between the EGFR/ERBB system and MYC/LRIG1 in the commitment of stem cells toward specific progenitor cell types, with implications for our understanding of their role in tissue development, homeostasis, and disease.

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An EGFR-ERK-SOX9 Signaling Cascade Links Urothelial Development and Regeneration to Cancer

Cited by 101 publications

References 47 publications

EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype

EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype

ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancer

Overexpression of Epigen during Embryonic Development Induces Reversible, Epidermal Growth Factor Receptor-Dependent Sebaceous Gland Hyperplasia

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