Mutant TP53 modulates metastasis of triple negative breast cancer through adenosine A2b receptor signaling

Abstract

PurposeThe identification of genes with synthetic lethality in the context of mutant TP53 is a promising strategy for the treatment of basal-like triple negative breast cancer (TNBC). This study investigated regulators of mutant TP53 (R248Q) in basal-like TNBC and their impact on tumorigenesis.Experimental DesignTNBC cells were analyzed by RNA-seq, and synthetic-lethal shRNA knock-down screening, to identify genes related to the expression of mutant TP53. A tissue microarray of 232 breast cancer samples, that included 66 TNBC cases, was used to assess clinicopathological correlates of tumor protein expression. Functional assays were performed in vitro and in vivo to assess the role of ADORA2B in TNBC.ResultsTranscriptome profiling identified ADORA2B as up-regulated in basal-like TNBC cell lines with R248Q-mutated TP53, with shRNA-screening suggesting the potential for a synthetic-lethal interaction between these genes. In clinical samples, ADORA2B was highly expressed in 39.4% (26/66) of TNBC patients. ADORA2B-expression was significantly correlated with ER (P < 0.01), PgR (P = 0.027), EGFR (P < 0.01), and tumor size (P = 0.037), and was an independent prognostic factor for outcome (P = 0.036). In line with this, ADORA2B-transduced TNBC cells showed increased tumorigenesis, and ADORA2B knockdown, along with mutant p53 knockdown, decreased metastasis both in vitro and in vivo. Notably, the cytotoxic cyclic peptide SA-I suppressed ADORA2B expression and tumorigenesis in TNBC cell lines.ConclusionsADORA2B expression increases the oncogenic potential of basal-like TNBC and is an independent factor for poor outcome. These data suggest that ADORA2B could serve as a prognostic biomarker and a potential therapeutic target for basal-like TNBC.

MALAT-1/p53/miR-155/miR-146a ceRNA circuit tuned by methoxylated quercitin glycoside alters immunogenic and oncogenic profiles of breast cancer

“…TP53 is the chief tumor suppressor protein and the most fundamental orchestrator of apoptosis and cell cycle arrest [37]. TP53 is markedly down regulated in TNBC patients and cell lines [34,38,39]. For that reason, TP53 was our primary target to unravel MQG molecular mechanism in TNCB cell lines.…”

Expression of Adenosine Receptors in Rodent Pancreas

“…The expression of A 2B adenosine receptors was increased in colon and breast cancer cells by hypoxia, suggesting a potential therapeutic target for cancer [40,42]. Indeed, selective A 2B adenosine receptor antagonists inhibited the proliferation of prostate, colon, and breast cancer cells [38,40,43]. The blockade of A 2B adenosine receptors was shown to increase the sensitivity of mouse GL261 glioma cells to the chemotherapeutic drug temozolomide [44].…”

Role of p53 in breast cancer progression: An insight into p53 targeted therapy

“…One such mechanism is the stabilization of mutant p53 protein by Rab coupling protein-mediated secretion of Hsp90 which enhances cell invasion and metastasis in cancer cells [36]. Mutant p53 also interacts with the G-protein coupled receptor, adenosine A2b receptor (ADORA2B) [37], and Pin1 [38]. Both interactions result in increased invasion and metastasis and are associated with poor clinical outcomes in breast cancer.…”