Triple negative breast cancer development can be selectively suppressed by sustaining an elevated level of cellular cyclic AMP through simultaneously blocking its efflux and decomposition

• DOI: 10.18632/oncotarget.13601
• Publication Date: 2016-11-25T17:52:49Z
• Authors: Wei Wang; Yue Li; Jessica Y Zhu; Dongdong Fang; Han-Fei Ding; Zheng Dong; Qing Jing; Shi-Bing Su; Shuang Huang
• Keywords: Triple-negative breast cancer; Cyclic adenosine monophosphate; Rolipram; IBMX; Efflux

Triple negative breast cancer (TNBC) has the highest mortality among all types and lack of targeted therapy is a key factor contributing to its high rate. In this study, we show that 8-bromo-cAMP, cyclic adenosine monophosphate (cAMP) analog at concentration (> 1 mM) selectively suppresses TNBC cell growth. However, commonly-used cAMP-elevating agents such as adenylyl cyclase activator forskolin pan phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) are ineffective. Inability cAMP elevating inhibit growth due rapid diminution cellular through efflux decomposition. By performing bioinformatics analyses with publically available gene expression datasets from patients/established lines further validating using specific inhibitors/siRNAs, reveal multidrug resistance-associated protein 1/4 (MRP1/4) mediate while members PDE4 subfamily facilitate When clearance prevented by inhibitors, blocks TNBC's in vitro arresting cycle G1/S phase. Importantly, cocktail forskolin, MRP probenecid rolipram vivo tumor development. This study suggests TNBC-targeted therapeutic strategy can be developed sustaining an elevated level simultaneously blocking