ATP-binding cassette (ABC) transporters are known to be multidrug resistance proteins that efflux various compounds out of cells including chemotherapeutic agents. A number of clinical trials have been conducted targeting ABCB1: however, none showed beneficial effects. The pleiotropic bioactive lipid mediator sphingosine-1-phosphate (S1P), which is generated by sphingosine kinase 1 (SphK1) inside breast cancer cells and exerts its functions by binding to its specific cell surface G-protein coupled receptors (S1PR1-5) after being exported, is now known as a key regulatory molecule in breast cancer progression. We have previously demonstrated that ABCC1 and ABCG2, but not ABCB1 export S1P out of MCF7 human breast cancer cells. We hypothesized that ABCC1 expression in the presence of S1P produced by activated SphK1 in human breast cancer is associated with poor prognosis.
We demonstrate the role of ABCC1 and SphK1/ S1P axis in breast cancer progression utilizing ABC transporter transduced breast cancer cell lines for in vitro and in vivo study. For clinical study, we analyze the expression of ABC transporters and S1P signaling factors utilizing a tissue microarray constructed from 276 breast cancer samples.
Overexpression of ABCC1 in breast cancer cell lines export more S1P. ABCC1 overexpression but not ABCB1 enhance proliferation and cell migration, and promote angiogenesis (AG) and lymph angiogenesis (LAG). MK571 which is inhibitor of ABCC1 suppress them. Overexpression of ABCC1 also aggravate tumor grow and contribute poor survival in syngeneic and xenograft mice model. In the clinical study, ABCC1 expression was associated with significantly shorter disease free survival (DFS) while ABCB1 was not. pSphK1 high expression group had significantly shorter DFS. Most of the patients expressed S1PR1; however, there were no significant differences in prognosis. Patients with tumors expressing both pSphK1 and ABCC1 had significantly shorter DFS, while patients expressing both ABCB1 and pSphK1 did not.
These translational findings suggest that inside-out signaling of S1P via ABCC1 may play a significant role in the course of human breast cancer progression.
This work was supported by grants from the National Institute of Health (R01CA160688 to K.T and R01CA61774 to S.S). M.N. is a Japan Society for the Promotion of Science Postdoctoral Fellow.
Citation Format: Akimitsu Yamada, Masayuki Nagahashi, Tomoyoshi Aoyagi, Wei C. Huang, Krista P. Terracina, Jeremy C. Allegood, Santiago Lima, Sheldon Milstien, Sarah Spiegel, Kumiko Kida, Takashi Ishikawa, Itaru Endo, Kazuaki Takabe. Activated SphK1 and export of S1P via ABCC1 shorten disease free survival in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1890. doi:10.1158/1538-7445.AM2014-1890