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

Abstract

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 ...

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

“…Supporting the previous study that proposed a FOSL1-dependent mechanism [11] in response to JQ1, our study suggests that FOSL1 and LEF1 might regulate transcription of non-BRD2 target genes presumably through BRD3 or BRD4. This result is consistent with the previous report that LEF1 acts as a coactivator in the presence of EP300 [45] and induces lung adenocarcinoma metastasis [46], while FOSL1 controls gene expression program mediating metastasis [47]. Since FOSL1 and LEF1 expression levels were reduced by JQ1 treatment, downregulation of their downstream target genes, such as IL6, FOS, and JUN, may lead to reduction of metastasis.…”

Tumor-infiltrating CD39+γδTregs are novel immunosuppressive T cells in human colorectal cancer

“…Recent studies have demonstrated that adenosine not only plays a crucial role in establishing immunosuppressive environment but also promotes tumor cell migration and metastasis directly through activation of its receptor. 39,40 In this study, we demonstrate that CD39 C gdTregs function via the adenosine-mediated pathway and are independent of TGF-b or IL-10. This inhibitory effect appears to function via CD73 and A2A or A2B receptor.…”

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

“…Several reports have connected Fra-1/AP-1 in human breast cancer to increased expression of the EMT-TFs Zeb1 and Zeb2 and to a lesser extent Slug. [12][13][14][15]17 We investigated whether Fra-1/AP-1 and the EMT-TFs also correlated in mouse mammary EMT. Expression of Fra-1 in EpH4 cells induced EMT and increased proliferation, migration and invasiveness.…”

“…10,11 Strikingly, suppression of Fra-1 restores epithelial characteristics, including E-cadherin expression, and abrogates the invasive potential of human breast cancer cell lines. 12,13 Furthermore, Fra-1 has been implicated in human breast cancer EMT through increased expression of the Snai2/Slug, Zinc finger E-box-binding homeobox 1 (Zeb1) and Zeb2 EMT-TFs, [13][14][15][16][17] although the mechanisms how Fra-1 modulates EMT-TFs expression are not fully understood.…”