Development of Short Term Hormone Treatments for Prevention of MNUinduced Mammary Carcinogenesis in Rats

The Protective Effect of Parity can be Mimicked by Short-term Treatment with E2 or E2 + P. Pregnant rats are exposed to very high circulatory levels of E2 and P that induce lobulo-alveolar differentiation in the mammary gland. To mimic this protective effect of pregnancy, we treated 7-week-old virgin rats with MNU followed by treatment with or perphenazine (PPZ, dopamine receptor inhibitor) for 3 weeks beginning at 9 weeks of age (10). Both of these treatments caused late pregnancy-like lobule development in mammary glands. 90% of the control rats, 73% ofthe PPZ-treated, and only 9% ofthe rats treated with sustained exposure to E2 + P in silastic capsules developed mammary cancer during the 9 mo-period of observation following MNU treatment. The E2 + P-treated rats developed 93% fewer MCs compared to controls not receiving hormonal treatment. Both PPZ and treatments induced, similar to pregnancy, lobular growth, secretory differentiation, and involution after cessation oftreatment ofthe mammary gland. Assays of blood levels of E2 and P indicate that after PPZ treatment, only the P levels (P = 101.5 ng/ml, E2 = 16.6 pg/ml,) were increased to pregnancy levels. There was no increase in circulating E2 levels compared to untreated control virgin rats (E2 = 18.3 pg/ml, P = 12.7 ng/ml). Treatmentwith E2 + P resulted in pregnancy levels of E2 (168.8 pg/ml), and lower than pregnancy levels of P (25.8 ng/ml). These circulating steroid levels are highly protective from MC. These studies suggested that pregnancy levels of are the likely reason for the protective effect of pregnancy against mammary cancer, and that lobular differentiation alone is insufficient to confer protection.

E2 Alone but Not P Induced Protection from Mammary Carcinogenesis. We tested the effect ofE2 or P administered singly for their ability to induce protection from MC (10). Rats were treated with MNU at 7 weeks of age. A silastic capsule containing 30 mg ofE2 or 30 mg P was implanted at 9 weeks of age and removed 3 weeks later. 100 % of the control rats developed mammary cancer by 9 mo (2.9

MCs/rat) after MNU treatment. E2 treatment alone provided protection from MC, 38% ofE2-treatedrats developed mammary cancer (0.5 cancers/rat). In contrast, P treatment enhanced MC in terms of cancer load compared to controls. 100% ofthe rats treated with P developed mammary cancer (3.6 cancers/rat). Treatment with a combination of 30 mg ofE2 and 30 mg ofP had the lowest incidence of mammary cancer (11%, 0.1 cancers/rat).

Pregnancy Levels of E2 Alone Induce Protection from Mammary Carcinogenesis. We have demonstrated that E2 alone or in combination with P is effective in preventing mammary cancer, while P alone is not. We determined the lowest dosage of E2 given alone that would be effective in preventing mammary cancer (11). Rats were injected with MNU at 7 weeks of age. Two weeks later, the rats were treated with 30 mg, 200 (ig, 100 jig or 20 fig of E2 in silastic capsules for three weeks. Blood levels of E2 immediately after treatments were 144,95,68, and 50 pg/ml, respectively. Untreated control rats had blood levels of 8-14 pg/ml of E2. The E2 blood levels from the 30 mg-, 200 |ng-, and 100 ng-treated rats were in the range found during pregnancy. Control rats had 100% mammary cancer incidence, 9.0 mo after treatment, while rats treated with 30 mg, 200 ng, or 100 (xg of E2had a cancer incidence ranging from 15 to 20%. The cancer incidence was not different from controls at the lowest E2 dose, but the multiplicity was reduced. The multiplicity of mammary cancers was 0.2 (30 mg), 0.3 (200 fig), 0.6 (100 ng), 1.2 (20 (ig), and 3.0 (controls). These results demonstrate that short-term treatments with doses of E2 equivalent to levels during second half of pregnancy (100 pg or higher) are highly effective in preventing mammary cancer. Treatment with equivalent to low pregnancy levels (100-200 (j.g) does not induce full lobulo-alveolar differentiation, yet it is highly effective in conferring protection. Studies have also shown that 1 or 2 weeks treatment with pregnancy levels of E2 (200 ng) and P (30 mg) in silastic capsule is highly effective in reducing the mammary cancer incidence in MNU-treated rats (11).

Short Term Protective Hormone Treatment has No Adverse Effects on the Health and Reproductive Physiology of Treated Rats. We examined whether short term treatment had any significant effects on the health and reproductive capabilities oftreated rats. Nulliparous rats were treated with 200 ng E2 + 30 mg P in silastic capsules from 9 to 12 weeks of age, and compared to age-matched controls treated with empty silastic capsules. This treatment is highly effective in preventing carcinogen-induced BC. All the hormone treated rats had regular estrous cycles 4-6 weeks after removal of the hormone treatment. Treated and control rats were mated at 16 weeks of age. Control rats had an average of 8 pups at birth and hormone-treated rats had 9. The weight of the pups was 5.9 and 6.0 g for control and treated rats, respectively. The weight at weaning was 35 g and 33 g for pups from control and treated rats, respectively. There were no significant differences in the monthly body weights of control or hormone-treated rats. The animals were necropsied at 600 days of age showing no difference in body weight, or pathology between control vs. the E2 + P treated rats.

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