Abstract P4-11-02: Mammary tumor formation induced by N-methyl-N-nitrosourea (MNU) is accelerated by natural and synthetic progesterone but suppressed by an anti-progesterone CDB4124

Abstract

Abstract Background: CDB4124, anti-progesterone suppresses the development of carcinogen-induced ER+/PR+ mammary tumors in rats, and may have implications for prevention and treatment of human breast cancer. We hypothesize that progesterone (P4) and medroxyprogesterone acetate (MPA) will accelerate mammary carcinogenesis induced by MNU, however CDB4124 will efficiently suppress tumor formation stimulated by progesterone. Methods: ovary intact female Sprague Dawley rats received a single intraperitoneal injection of 50mg/kg MNU at 4-5 weeks of age. 30mg of CDB4124 and 25mg of P4 or MPA (90 release pellets, Innovative research of America, Inc) were implanted in dorsal area at 3 weeks and 4 weeks after MNU injection, respectively. 10-11 rats were used for each treatment group. Tumor incidence, latency, multiplicity, and burden were recorded weekly. 9 weeks after MNU injection all the mice were euthanized and mammary tumors and glands were fixed in 10% (v/v) neutral buffered formalin. Plasma concentrations of CDB4124 and its metabolite CDB4453 were determined by LC-MS/MS. Results: The first tumor appeared in the control group at 5 weeks, and in the P4 and MPA treated groups at 6 weeks after MNU injection. 7 weeks after MNU injection, mammary tumor incidence of MPA and P4 treated groups were 80% and 50%, respectively compared to 30% in the control group. 9 weeks after MNU injection all MPA treated mice, 80% of P4 treated mice, and 60% of control mice developed tumors. Tumor incidence, latency, multiplicity, and tumor weight were summarized as mean ± SD in Table 1. [Table 1] Tumor latency, incidence, multiplicity, and burden in mammary tumorsTreatmentsLatency (days)Incidence(%)MultiplicityBurden (g)Control53.7 ± 12.9602.34.25 ± 7.02P453.6 ± 9.6802.64.11 ± 5.32MPA50.8 ± 7.71002.56.02 ± 4.85P4 + CDB412459.3 ± 11.53621.38 ± 0.61MPA + CDB412454.3 ± 10.7732.84.19 ± 4.39 Tumor latency of CDB4124 treated groups was increased; tumor incidence and burden (g) of CDB4124 treated groups were decreased compared to P4 and MPA treated groups. In particular, tumor incidence and burden of CDB4124 + P4 treated group were significantly lower than those of the control group. Plasma CDB4124 and CDB4453 were 11.6 ±5.88 ng/mL and 3.4±1.68 ng/mL, respectively. Histopathology of tumors and mammary glands and immuno-histochemical evaluations of Ki67, activated caspase-3, CD34, ER, and PR are currently underway. Conclusions: Our results indicated that natural progesterone promotes MNU- induced mammary tumor formation similar to synthetic progesterone, MPA in rats. Under this tumor permissive environment, CDB4124 provided excellent prevention efficacy, suggesting good potential as breast cancer prevention agent. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-11-02.