Reduced self-renewal ability and drug resistance by inhibition of notch-4 and ABCG2 in anoikis-resistant MDA-MB-231 breast cancer cells.

Abstract

Abstract Abstract #5059 Background In this study, we aimed to investigate the effect of anoikis resistance on drug responsiveness and tumor initiating ability in MDA-MB-231 breast cancer cell line, and to determine whether ABCG2 inhibitor and notch-4 inhibitor will modulate the drug resistance and self renewal ability of anoikis-resistant cells. Methods Anoikis-resistant MDA-MB-231 cells isolated from the MDA-MB-231 cell line using sequential passages through the floating culture system and tested the tumor initiating ability (mammosphere-forming efficacy in vitro and limiting dilution transplantation in vivo), tumor growth rate, and drug responsiveness. Results Anoikis resistant cells were shown to have a greater mammosphere forming efficacy than parent cells (19% versus 2%, P<.001). Similarly, both tumor formation rate and growth rate of anoikis-resistant cells were greater than parent cells when injected into NOD/SCID mice. Anoikis resistant cells were also more resistant to doxorubicin and docetaxel than parent cells. Immunoblots shown that expression of ABCG2 and notch-4 increased in anoikis-resistant cells as compared to parent cells. ABCG2 inhibitior (fumitremorgin C) and notch-4 inhibitor (gamma secretase) were found to preferentially reduce drug resistance and mammosphere-forming efficacy of anoikis resistant cells, respectively. Conclusion Acquisition of anoikis resistance in human breast cancer cells results in increased tumor initiating ability, tumor growth rate and resistance to chemotherapeutic agents. The increased expression of notch-4 and ABCG2 may provide an explanation for the increased tumor initiating ability and drug resistance in anoikis resistant cells. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5059.