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Neumann et al. J Cancer Metastasis Treat 2018;4:13 I http://dx.doi.org/10.20517/2394-4722.2017.60 Page 5 of 7

promising immunotherapeutic option for a group of TNBC patients. Regulatory T-cell depletion
has been recently been shown to potentiate the inhibition of the immune checkpoint in claudin-low
[35]
breast cancers, a subgroup of breast cancer that is largely found within the TNBC group of patients .
Besides suppressing immune responses in TNBC, some studies suggest a A2BR immune independent
function in breast cancer progression. For example, adenosine stimulates proliferation and migration of
human TNBC cells through A2BR-mediated stimulation of adenylyl cyclase/PKA and a PLC-dependent
Ca(2+) signal [36,37] . Selective pharmacological activation of A2BR promoted tumor cell chemotaxis in vitro
and metastasis in vivo using a syngeneic TNBC mouse model (4T1.2 cells). In contrast, the A2BR antagonist
PSB1115 reversed significantly both phenotypes. As 4T1.2 cells express exclusively A2BR, the authors
[38]
[39]
concluded that expression on A2BR on cancer cells contributes to breast cancer metastasis . Mittal et al.
confirmed these findings by showing that inhibition of A2RB in vivo, using the 4T1.2 mouse model was
+
+
independent of CD4 or CD8 T-cells and/or natural killer cells in this setting. A synthetic lethality screen
identified a pharmacological axis that identifies A2BR as a target gene of the transcription factor Fos-
related antigen-1 that promotes TNBC metastasis. In this model, both RNAi silencing and pharmacological
inhibition of A2BR inhibited filapodia formation and invasive activity of TNBC cells and correspondingly
[40]
reduced tumor outgrowth in the lungs in an immune-compromised mouse model .

FUTURE DIRECTIONS
Tumor hypoxia is an unavoidable byproduct of fast and aggressive growing tumors, and the hypoxic response
[41]
is quite robust in TNBC compared to other subtypes . Deprivation of oxygen induces the accumulation of
[25]
extracellular adenosine in tumors providing abundant ligand for adenosine receptors, such as A2BR . A2BR
expression is higher in basal-like breast cancers compared to other breast cancer subtypes [Figure 2] and
A2BR is a major player in immune suppression, metastasis and relapse in TNBC. Therefore, A2BR provides
an attractive target for treating TNBC, for which currently no targeted therapies exist. In particular the
combination of immune checkpoint inhibitors together with A2BR agonists should be considered as viable
[42]
treatment option, as checkpoint inhibitors show promising results in phase 1/2 clinical trials in TNBC .
Besides presenting a viable drug target, A2BR may also serve as a prognostic biomarker in TNBC. More
studies need to be done to test this hypothesis. Not unlike in other drug targeting strategies, more research is
necessary to develop molecular and pathological parameters upfront that define appropriate patient cohorts
that should be tested for anti-A2BR therapies. For example, TNBC subtyping shows how heterogeneous
TNBC subtypes are. In addition, analyses are necessary to determine A2BR antagonistic effects on TILs
in TNBC and patient outcome. In summary, based on current research, A2BR may present a viable drug
candidate in a defined cohort of TNBC breast patients.

DECLARATIONS
Authors’ contributions
Wrote the manuscript: Neumann CA
Developed the METABRIC expression and analysis tool: Levine K, Oesterreich S

Financial support and sponsorship
None.

Conflicts of interest
There are no conflicts of interest.

Patient consent
Not applicable.