P3-10-02: Gene Expression Changes in Methylnitrosourea (MNU)-Induced ER+ Mammary Cancers Following Short-Term Treatment of Rats with the Aromatase Inhibitor Vorozole.

Abstract

Abstract Aromatase inhibitors have proven to be highly effective in both therapy and prevention of ER+ breast cancer. Vorozole (R83842), a high affinity competitive inhibitor of aromatase (similar to letrozole and anastrozole) showed strong activity in early clinical trials against ER+ breast cancer. Furthermore, vorozole was highly effective in the prevention and therapy of ER+ cancers in the MNU-mammary cancer model (Lubet, et al., Carcinogenesis 19, 1345, 1998). In the present study, rats bearing mammary cancers induced by MNU were exposed to vorozole (1.25 mg/kg BW/day) for 5 days. Global gene expression analysis showed that 162 genes were down-regulated and 180 genes up-regulated in cancers treated with vorozole (p < 0.05 and fold change > 1.5). The genes modulated by vorozole were compared with two additional sets of data. First, thirty-two genes and a number of pathways exhibited significantly concordant changes with aromatase inhibitors both in the animal model and in at least three of four published human data sets. In particular, differentially expressed genes enriched in the cell cycle pathway that were related to chromosome condensation in prometaphase [including Aurora-A, Aurora-B, Bub1B, non-SMC condensin I complex, subunit H (BRRN1), Condensin, CAP-G, CAP-G/G2, CAP-H/H2, CAP-D2/D3, CAP-E, TOP2, Cyclin A, Cyclin B, CDK1, Histone H1 and inner centromere protein (INCENP)] were downregulated after treatment with the aromatase inhibitor. These results appear to be in agreement with the strong anti-proliferative effects of aromatase inhibitors in both animal and clinical studies. A second comparison was with an in vitro study in which estrogen was removed from MCF-7 cells in culture. Decreases in genes related to the E2F1 transcription factor were observed. In our study, 13 modulated genes exhibited E2F-1 binding sites in their promoter regions, and 7 genes contained both ER binding and E2F binding sites. We were able to confirm modulation of the cell cycle related and E2F-related genes in a large independent set of human samples treated with anastrozole. The results on RNA changes for Bub 1B, Cyclin A and CDK-1 were verified by employing IHC analysis. In summary, gene changes observed in the rat closely paralleled gene changes associated with aromatase treatment and estrogen withdrawal in humans. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-10-02.