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Ovarian-dependent Growth of p53-null Normal Mammary Epithelium. The growth ofthe p53-null mammary epithelium was absolutely dependent on ovarian hormones as the cells did not exhibit expansive growth in ovariectomized (ovx) mice (Figure 1). The growth of p53-null mammary epithelium in ovx mice was inhibited to the same extent as the growth of p53-wt epithelium (84% vs. 77%, respectively; P > 0.05). Thus, in these assays and those previously reported, the p53-null normal mammary epithelium behaved similarly to the p53-wt normal mammary epithelium. The p53-null mammary epithelium at 8-12 weeks post transplantation exhibits a normal distribution and cellular localization ofERa and PR. At 8 weeks post transplantation, the ERa score for wt and p53-null epithelium was 5-6 on a scale of 8, using the system described in (8).

Figure 1. Growth of normal mammary duct transplants in ovx mice. There were 8

transplants/group. Mice were ovx at 5 weeks of age and mammary transplants were analyzed as whole mounts at 11 weeks of age. (Reproduced with permission from Cancer Research.)

Figure 1. Growth of normal mammary duct transplants in ovx mice. There were 8

transplants/group. Mice were ovx at 5 weeks of age and mammary transplants were analyzed as whole mounts at 11 weeks of age. (Reproduced with permission from Cancer Research.)

Hormone-induced Tumorigenesis in p53-null Mammary Epithelium. Previous results demonstrated that hormones provided by a pituitary isograft (P and PLN) induce normal morphogenesis in p53-null mammary epithelium (3). The results in Table 1 show that chronic levels of E2 and P, administered singly, markedly enhanced tumorigenesis compared to the untreated group. There were no significant differences in tumor incidences or tumor latencies among the different hormone treatment groups (P > 0.05). In contrast, ovariectomy at 5 weeks of age almost totally blocked tumorigenesis (Table 1) and resulted in a tumor incidence less than that in untreated mice (P < 0 .05).

Table 1. Hormone-induced Tumorigenesis in p53-null Mammary Epithelium.

Tumorigenesis in Progesterone Receptor-deficient Mammary Epithelium. The marked dependence on P-mediated signaling for tumorigenesis was tested directly by cross-breeding the p53-null mice with FVB PRKO mice to generate p53 -/-, PR -/- mammary ducts. The results in Table 2 show that mammary tumorigenesis in hormone-stimulated p53-null epithelial cells was markedly reduced in the absence of P signaling (i.e., when the PR was deleted) from 84% to 32%. In these mice, P levels are high due to the PLN secreted by the pituitary isograft.

Tamoxifen Inhibition of p53-null Mammary Tumorigenesis. The tumorigenic response ofthe p53-null mammary epithelium is shown in Figure 2. The presence of a pituitary isograft increased the tumorigenic response (p < 0.05) compared to that ofuntreated epithelium [26 of 28,93%, TE50(50% tumor endpoint) = 36 weeks vs. 10 of 28, 36%, TE50 > 58 weeks, respectively]. The addition of tamoxifen completely eliminated the enhanced tumorigenic response induced by the chronic hormone stimulation (Tam. = 11 of 28, 39%, TE50 > 58 weeks), so this group effectively behaved like the untreated group. Of interest, 30% of the tumors were in the untreated group, while no arose in the tamoxifen treated group.

Table 2. Tumorigenesis in p53-null and PR-deficient Mammary Epithelium.

No. of Tumors/No. of Group_Transplants (%)_TE50 (weeks)

1 pit, pituitary isograft.

Figure 2. Effect of tamoxifen on tumorigenesis in BALB/c p53-null mammary epithelium.

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