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.
Highlights
triple negative breast cancer (TNBC) is clinically aggressive and difficult to treat
The identification of genes that have synthetic lethality with mutant TP53 is a promising approach in this regard, since TP53 mutations occur in approximately 40% percent of all breast cancers, with the highest frequency found in the basal-like (80%) and Human epidermal growth factor receptor 2 (HER2)-enriched (72%) subtypes of TNBC, and the lowest found in the Luminal A (12%) and Luminal B (29%) subtypes [3, 4]
To identify a therapeutic target for patients with TNBC, we focused on basal-like cases carrying the R248Q TP53 mutation, which is expressed in TNBC, and initially performed a pre-screening whole transcriptome analysis (RNA-seq) to identify important genes
Summary
TNBC is clinically aggressive and difficult to treat. One of the reasons for the failure to develop new therapies for this subgroup of breast cancer patients has been the difficulty in identifying highly prevalent, targetable molecular alterations in these tumors [1]. The validation of a targeted therapy approach for patients with TNBC is urgently needed [2]. Breast cancers carrying mutations in TP53 are characterized by an aggressive and metastatic phenotype with the poorest outcomes [5]. Mutations at five known hotspots in TP53 (V143A, G245S, R248Q, R249S and R273H) are frequently associated with gain-of-function (GOF) phenotypes [6], it is the loss of p53 function that is more generally considered to play an essential role in carcinogenesis and disease progression [7, 8]
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