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Ovariectomized August Copenhagen Irish (ACI) rats were treated with various doses and combinations of 17-beta-estradiol (E) and progesterone (P) to determine the role of ovarian steroids in promoting mammary carcinogenesis. This study is relevant to human breast cancer since as shown by the laboratories of Schull (Harvell et al, Proc. Natl. Acad. Sci. 97, 2779, 2000) and Li (Weroha et al.,Carcinogenesis 27, 491, 2006) that these estrogen induced tumors exhibit aneuploidy as do invasive ductal mammary carcinomas in women. Li’s laboratory has found that with time small focal dysplasia are seen followed by large focal dysplasias with atypical ductal hyperplasia, then DCIS and finally frank tumors appear. Previous studies by the laboratories of Schull et al (Carcinogenesis 18:1595, 1997) and S. A. Li et al (J. Endocrinol. 175: 297, 2002) have shown that when a 27.5 mg silastic capsule or 3 mg pellet of E, respectively, is implanted into intact female ACI rats, mammary tumors are seen within 3-4 (Schull) and 5-6 months (Li, ). Schull also noted that implantation of E capsules failed to induce tumors in ovariectomized ACI rats. This suggests that the ovarian hormone, P maybe required for mammary carcinogenesis in ACI rats. In this study we investigated along with high dose E the use of a low dose of E with and without P or with E and P with testosterone proprionate (TP). Virgin ACI rats were ovariectomized at 5 weeks of age and at 6 weeks were implanted with silastic capsules and divided into 7 groups of 15 each: (1) control capsules with no hormone, (2) 10 ug E, (3) 10 ug E + 30 mg P, (4) 30 mg E, (5) 30 mg E + 30 mg P, (6) 30 mg E + 30 mg P + 30 mg TP and (7) 30 mg P. At 5.5 months after the start of hormonal treatment it was noted that the groups with 30 mg E or 30 mg E + 30 mg P but not 30 mg E + 30 mg P + 30 mg TP were often sickly with reduced weight. Therefore, we switched to 3 mg E capsules for the remainder of the study for groups 3, 5 and 6. Capsules in all groups were changed every 60 days for the duration of the experiment. Groups 1 through 4 and 7 showed no tumor incidence and no weight loss. Tumors began to appear in groups 5 (E + P)and 6 (E + P + TP)at 140 days with latencies of 161 ± 7 and 171 ±7 days, respectively, and in not any other group at 7.5 months following the start of hormonal treatment. Groups 5 and 6 showed tumor incidence of 60% and 53% and multiplicities of 1.3 and 0.87 tumors per rat group. The majority of the tumors in Group 5 appeared before switching from 30 mg E to 3 mg E. In conclusion, this study shows the absolute requirement for P along with E in mammary carcinogenesis in highly susceptible ovariectomized ACI rats that is not counteracted by the presence of testosterone. Supported by California Breast Cancer Research Program Grant 8PB-0132

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA