Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

Sayan, Emre; Stanford, Richard Fj; Vickery, Robert K.; Grigorenko, Elena; Diesch, Jeannine; Kulbicki, K; Edwards, Richard E.; Pal, Rekha; Greaves, Peter; Jariel-Encontre, Isabelle; Piechaczyk, Marc; Kriajevska, Marina; Mellon, J. Kilian; Dhillon, Amardeep S.; Tulchinsky, Eugene

doi:10.1038/onc.2011.336

Cited by 99 publications

(91 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6). In line with this, Fra-1 has been shown to be involved in the migratory or invasive capabilities of various cancer cell lines (36,37). Furthermore, in rodent model systems, Fra-1 was identified as a key regulator of metastasis (35).…”

Section: Discussionmentioning

confidence: 70%

Genome-wide Profiling of AP-1–Regulated Transcription Provides Insights into the Invasiveness of Triple-Negative Breast Cancer

et al. 2014

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties. Cancer Res; 74(14); 3983-94. Ó2014 AACR.

show abstract

Section: Discussionmentioning

confidence: 70%

Genome-wide Profiling of AP-1–Regulated Transcription Provides Insights into the Invasiveness of Triple-Negative Breast Cancer

et al. 2014

View full text Add to dashboard Cite

show abstract

“…40). In bladder cancer, FRA-1 promotes AXL transcription that mediates FRA-1 effect on cancer cell motility (41). Our findings that in TNBC cell lines AXL activation by GAS6 increases FRA-1 expression and FRA1 knockdown abolishes SNAIL and ZEB1 upregulation by GAS6/AXL signaling bring new insights into the cross-talk between these proteins in EMT signaling.…”

Section: Discussionmentioning

confidence: 79%

Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis

Leconet

Chentouf

Manoir

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: AXL receptor tyrosine kinase has been described as a relevant molecular marker and a key player in invasiveness, especially in triple-negative breast cancer (TNBC).Experimental Design: We evaluate the antitumor efficacy of the anti-AXL monoclonal antibody 20G7-D9 in several TNBC cell xenografts or patient-derived xenograft (PDX) models and decipher the underlying mechanisms. In a dataset of 254 basal-like breast cancer samples, genes correlated with AXL expression are enriched in EMT, migration, and invasion signaling pathways.Results: Treatment with 20G7-D9 inhibited tumor growth and bone metastasis formation in AXL-positive TNBC cell xenografts or PDX, but not in AXL-negative PDX, highlighting AXL role in cancer growth and invasion. In vitro stimulation of AXL-positive cancer cells by its ligand GAS6 induced the expression of several EMT-associated genes (SNAIL, SLUG, and VIM) through an intracellular signaling implicating the transcription factor FRA-1, important in cell invasion and plasticity, and increased their migration/invasion capacity. 20G7-D9 induced AXL degradation and inhibited all AXL/GAS6-dependent cell signaling implicated in EMT and in cell migration/invasion.Conclusions: The anti-AXL antibody 20G7-D9 represents a promising therapeutic strategy in TNBC with mesenchymal features by inhibiting AXL-dependent EMT, tumor growth, and metastasis formation.

show abstract

“…In vitro, Fra-1 has been shown to be involved in the migratory or invasive capabilities of various cancer cell lines (18)(19)(20). Therefore it has long been suspected that Fra-1 may play an important role in metastasis (21).…”

Section: Gene-expression Profiling and Functional Perturbation In A Mmentioning

confidence: 99%

“…Fra-1 frequently is overexpressed in human solid tumors as well as in many cell lines derived from such tumors (20,21,(25)(26)(27)(28). To investigate whether Fra-1 has a more general role in metastasis, we focused on human breast cancer, in which several lines of evidence suggest a role for Fra-1 in metastatic disease.…”

Section: Suppression Of Fra-1 Abrogates the Metastatic Potential Of Hmentioning

confidence: 99%

Identification of a pharmacologically tractable Fra-1/ADORA2B axis promoting breast cancer metastasis

Desmet

Gallenne

Prieur

et al. 2013

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

157

149

View full text Add to dashboard Cite

Metastasis confronts clinicians with two major challenges: estimating the patient's risk of metastasis and identifying therapeutic targets. Because they are key signal integrators connecting cellular processes to clinical outcome, we aimed to identify transcriptional nodes regulating cancer cell metastasis. Using rodent xenograft models that we previously developed, we identified the transcription factor Fos-related antigen-1 (Fra-1) as a key coordinator of metastasis. Because Fra-1 often is overexpressed in human metastatic breast cancers and has been shown to control their invasive potential in vitro, we aimed to assess the implication and prognostic significance of the Fra-1-dependent genetic program in breast cancer metastasis and to identify potential Fra-1-dependent therapeutic targets. In several in vivo assays in mice, we demonstrate that stable RNAi depletion of Fra-1 from human breast cancer cells strongly suppresses their ability to metastasize. These results support a clinically important role for Fra-1 and the genetic program it controls. We show that a Fra-1-dependent gene-expression signature accurately predicts recurrence of breast cancer. Furthermore, a synthetic lethal drug screen revealed that antagonists of the adenosine receptor A 2B (ADORA2B) are preferentially toxic to breast tumor cells expressing Fra-1. Both RNAi silencing and pharmacologic blockade of ADORA2B inhibited filopodia formation and invasive activity of breast cancer cells and correspondingly reduced tumor outgrowth in the lungs. These data show that Fra-1 activity is causally involved in and is a prognostic indicator of breast cancer metastasis. They suggest that Fra-1 activity predicts responsiveness to inhibition of pharmacologically tractable targets, such as ADORA2B, which may be used for clinical interference of metastatic breast cancer.epithelial-mesenchymal transition | invasion T he path toward improved management of metastatic tumors, the major cause of death among cancer patients, involves tackling of two major challenges: the development of therapies that combat the patient's metastatic disease and of means of reliably assessing the individual patient's risk of developing metastasis. In line with the second objective, patient stratification has received increasing attention as a way to improve the therapeutic management of cancer patients. In recent years, for example, gene-expression profiling of primary breast cancer has uncovered gene signatures that assist clinicians in classifying breast cancer subtypes more accurately (1, 2) and that provide predictions of tumor recurrence and clinical outcome (3-5). Such classifiers have proven useful for formulating prognosis and adjusting therapeutic management of breast cancer patients, complementing conventional histopathological criteria such as tumor size, nodal status, and estrogen receptor (ER) status (6-8) to predict clinical outcome better.The most important challenge posed by metastatic cancer, blocking metastatic spread, has proven more troublesome. Indeed, most ...

show abstract

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

Cited by 99 publications

References 43 publications

Genome-wide Profiling of AP-1–Regulated Transcription Provides Insights into the Invasiveness of Triple-Negative Breast Cancer

Genome-wide Profiling of AP-1–Regulated Transcription Provides Insights into the Invasiveness of Triple-Negative Breast Cancer

Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis

Identification of a pharmacologically tractable Fra-1/ADORA2B axis promoting breast cancer metastasis

Contact Info

Product

Resources

About