Abstract P2-03-07: Backwards translation: Exploring beta-adrenoreceptors (ßAR) in triple negative breast cancer (TNBC), a novel and druggable pathway

Abstract

Abstract Introduction: several retrospective studies suggest that ßAR blocking drugs (BB) are associated with improved survival in patients with a wide range of cancers. Recently, we retrospectively showed an association between BB intake and improved progression free survival in patients with HER2 negative advanced breast cancer (BC), particularly striking in triple-negative disease (TNBC) (Reference). Based on this finding we decided to conduct an in silico study in which we have interrogated ßARs in a publicly available BC sample database and the Translational Oncology Research Lab (TORL) translational platform with a genomic, transcriptomic and proteomic approach. Methodology: genomic and transcriptomic data sets for ßAR 1, 2 and 3 were retrieved from cBioPortal considering all BC samples available with this information in The Cancer Genome Atlas (TCGA). Transcriptomic and proteomic data sets from 48 BC cell lines obtained from TORL were queried for ßARs as well and used with validation and exploratory intent. Mutations, amplifications and deletions were queried in DNA; gene expression profiles were interrogated using RNAseq data together with protein expression by RPPA. Average expression, log ratio and fold change in mRNA and Reverse Phase Protein Array (RPPA) quantitative assessments for corresponding proteins were noted. BC cell lines with top 10 mRNA and protein levels of ßAR 1, 2 and 3 were identified. Results: CBioPortal DNA data shows ß AR1 amplified in 1-10% and deleted in 0,4%; ß-AR2 amplified in 1-3% and deleted in 0,1%; ß-AR3 amplified in 15-20% and deleted in 2% of the BC samples. CBioPortal mRNA data shows ß-AR1 is upregulated in 2.7% (mostly Progesterone Receptor negative BC); ßAR2 is upregulated in 4% (mostly TNBC); ßAR3 is upregulated in 4% (mostly HER2 negative BC) in BC samples. TORL cell line panel shows that ßARs are heterogeneously expressed between the BC cell lines (fold change range: ßAR 1 2.015-3.636; ßAR2 2.545-8.248; ßAR3 1.809-2.444). Within the 10 BC cell lines with highest ßAR1 and ßAR2 expression, 7(COLO-824, HCC1937, BT-549, BT-20, HCC1599, HCC1143, HCC1806) and 6 (184A1, MDA-MB-231, 184B5, HCC1806, MCF-10A and MDA-MB-468) of them respectively correspond to the basal BC subtype. RPPA identifies caveolin 1, PAI 1, EGFR and Bax as the proteins with the higher co-expression with ßAR1 and ßAR2. Conclusions: DNA alterations are infrequent in ßARs in BC samples. Transcriptional mRNA data from BC samples shows ßARs mostly expressed in non-luminal BC subtypes, being ßAR 2 the one with highest expression. In silico data results from BC cell line panel show ßAR 1 and ßAR 2 are highly expressed in basal BC subtype. The above data suggest that ßAR, and ßAR 2 in particular could be a relevant target to explore in in vivo BC models. Table 1:mRNA and RPPA in BC cell linesCell lineAverage mRNALog RatioFold ChangeCaveolin 1PAI1EGFR184A1313173.048.244.183.411.72SUM-190223292.811.03-1.37-0.570.09MDA-MB-231151002.997.993.853.251.57184B5130121.973.933.902.361.82HCC1806124112.375.193.750.491.67MCF-10A119122.194.583.892.670.08ZR-75-3093001.893.72-1.51-0.61-0.25JIMT-163541.593.013.082.010.81MDA-MB-41562391.242.370.96-0.39-0.13MDA-MB-46862801.342.541.06-0.251.72 Citation Format: Spera G, Von Euw E, Fresco R, Slamon DJ. Backwards translation: Exploring beta-adrenoreceptors (ßAR) in triple negative breast cancer (TNBC), a novel and druggable pathway [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-03-07.