Abstract P1-08-02: Gene expression changes in methylnitrosourea (MNU)-induced ER+ mammary cancers following short-term treatment of rats with SERMs (Tamoxifen and Arzoxifene)

Abstract

Abstract SERMs have proven to be highly effective in both therapy and prevention of ER+ breast cancers. Tamoxifen has been the most commonly used SERM, but arzoxifene (another high- affinity competitive SERM agonist) showed strong activity in early clinical trials against ER+ breast cancer; although further development was discontinued. Both SERMs have shown a dose dependent effect on prevention and therapy of rat mammary tumors in the ER+ MNU model of cancer. Of interest, the doses required for prevention was significantly lower than the doses required for therapy. In the present study, rats bearing mammary cancers induced by MNU were treated with tamoxifen (0.66, 3.3, 20 and 100 ppm in diet) or arzoxifene (3.0 ppm in diet) for 5 days. Global gene expression analysis showed that more than 100 genes were down-regulated and more than 100 genes were up-regulated (p < 0.05 and fold change >1.5) in cancers treated with tamoxifen doses > 3 ppm; and that many of these gene changes were dose dependent. The genes modulated by tamoxifen and arzoxifene were enriched in the cell cycle pathway that were related to chromosome condensation in prometaphase [including Aurora-A, Aurora-B, Bub1B, non-SMC condensing 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 inter-centromere protein (INCENP]. Employing a different set of tamoxifen treated samples, we were able to confirm that many of the same genes were modulated employing a quantitative RT-PCR assay. Finally, we will compare certain of the gene changes obtained in the animal model with gene changes observed in human neoadjuvant trials. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-08-02.