Abstract 1357: Inhibition of breast cancer cell growth by a synthetic ligand targeting the nuclear receptor, REV-ERB (NR1D1 and NR1D2)

Abstract

Abstract Disruption of the circadian rhythm leads to increased risk for development of breast cancer in humans. The molecular mechanism underlying the link between circadian rhythm disruption and the increased risk of breast cancer in humans is not clear. The REV-ERBs are nuclear receptors that function as critical regulatory components of the circadian rhythm. We observed that REV-ERBbeta is highly overexpressed in multiple breast cancer cell lines, but not in the non-tumorigenic control breast cell line, MCF-10A. Furthermore, we show that a synthetic REV-ERB agonist that we discovered, SR9011, inhibits the proliferation of multiple breast cancer cell lines including triple negative breast cancers but has no effect on MCF10A cells. We discovered that the REV-ERBs directly regulates the expression of cyclin A2 gene suggesting a possible mechanism for inhibition of proliferation. Treatment of breast cancer cell lines with SR9011 repress the expression of cyclin A2 at both mRNA and protein levels. SR9011 treated SKBR3 cells display a reduced fraction of cells in S phase and in the G2/M phase. Administration SR9011 to synchronized SKBR3 cells results in about 8 hours delay of G2/M phase occurrence. Thus, our data suggests that REV-ERB is a valid target for development of anti-cancer agents and SR9011 holds promise for treatment of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1357. doi:10.1158/1538-7445.AM2011-1357