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

Wei Wang, Yue Li, Jessica Y. Zhu, Dongdong Fang, Hanfei Ding, Zheng Dong, Qing Jing, Shi Bing Su, Shuang Huang

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)87232-87245
Number of pages14
JournalOncotarget
Volume7
Issue number52
DOIs
StatePublished - Jan 1 2016

Fingerprint

Triple Negative Breast Neoplasms
Cyclic AMP
Colforsin
Breast Neoplasms
Growth
Phosphodiesterase 4 Inhibitors
Rolipram
8-Bromo Cyclic Adenosine Monophosphate
1-Methyl-3-isobutylxanthine
Probenecid
Phosphodiesterase Inhibitors
Mortality
G1 Phase
Computational Biology
S Phase
Adenylyl Cyclases
Cell Cycle
Gene Expression
Cell Line

Keywords

  • Cell growth
  • MRP
  • PDE
  • TNBC
  • cAMP

ASJC Scopus subject areas

  • Oncology

Cite this

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. / Wang, Wei; Li, Yue; Zhu, Jessica Y.; Fang, Dongdong; Ding, Hanfei; Dong, Zheng; Jing, Qing; Su, Shi Bing; Huang, Shuang.

In: Oncotarget, Vol. 7, No. 52, 01.01.2016, p. 87232-87245.

Research output: Contribution to journalArticle

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