Aromatase Transgenic Mice are Susceptible to Carcinogens

To test the hypothesis that tissue E-induced preneoplastic changes induced may be susceptible to carcinogens like DMBA, and that exposure to these carcinogens may result in acceleration and/or increase in the incidence of BC (21). Exposure to a single sub-threshold concentrations of DMBA (0.5 (ig/mouse) resulted in development of MG tumors in 25-1 of the transgenic animals and non in wild type mice. All the DMBA-exposed transgenic females had microscopic evidence of tumor formation/neoplastic progression. When the ARO transgenic female animals were exposed to a higher DMBA dose (1.0 Hg/mouse/week/4 weeks), more than 50% developed palpable MG tumors within 4.0 mo, while 100% show microscopic evidence of tumor formation within the same time period, compared to non-transgenic littermates (Table 1). Increased EGFR expression and its ligands, most notably TGFa, in DMBA-induced MG tumors, suggest a synergistic role of these growth factors in tumor progression and consistent with other studies showing the involvement of increased levels of EGFR and its ligands in BC (23, 24).

Table 1. Tumor Incidence in Aromatase Transgenic Mice After DMBA Exposure.

Tumors1"2

Microscopic Tumors1,2

Adenocarcinoma1,2

DCIS/ Hyper-plasia1,2

Wild type

(11 = 25)

0

0

0

0

17

Aromatase

(n = 16)

60

100

45

30

100

1 4.0 mo after the last dose of DMBA exposure.

2 % number of mice with tumors and tumor types

1 4.0 mo after the last dose of DMBA exposure.

2 % number of mice with tumors and tumor types

Previous data (6, 13, 22) suggest that the ERa has a negative regulatory effect on EGFR expression and its ligands. These results are consistent with the clinical observations that loss of ERa in BC results in the upregulation of growth factors like TGFa, leading to a more aggressive progression of the disease. We e observed changes in expression between DMBA-treated and untreated ARO transgenic mice. These findings exclude the possibility that the increased TGFa is due to the downregulation of ERa. One possible explanation is the alteration of other factors involved in ERa-mediated regulation, leading to the loss of ERa negative control on TGFa expression. Another explanation to consider is that the levels of E2, and consequently activated E2-bound ER, may be possibly decreased due to the metabolic conversion of E2 to catechols and OH-Es as part of the carcinogenic process.

High-doses of exogenous Es are associated with experimental BC (25). Exogenous Es significantly enhance or promote the carcinogenic effects of other chemical carcinogens, such as DMBA, and consequently, they may enhance MG carcinogenicity. This synergy between E and DMBA in the development of MG tumors was also observed in these studies. Tumors were observed only in DMBA-treated ARO-overexpressing mice, but none in similarly treated non-transgenic or in untreated ARO transgenic mice. Only preneoplastic changes, i.e., ductal hyperplasia, were observed in the untreated ARO transgenic mice (12, 13). These observations point to the involvement of ARO overexpression, and the resulting increase in E levels, in the development of MG hyperplasia. DMBA may act at this stage, with a larger population of epithelial cells susceptible to mutagenesis, further enhancing the observed estrogenic effects in the DMBA-treated ARO-overexpressing mice. On the other hand, DMBA may act as the initiator in the MGs of the treated ARO-overexpressing mice, and that the continuously elevated E levels promote tumor development in these mice.

Recently, several lines of evidence (26-28) suggested a role for E2 (non ER-mediated) and its metabolites in genotoxic effects leading to carcinogenesis, which includes oxidative stress and adduct formation. Since no changes were observed in expression in the DMBA-treated ARO transgenic mice, it is possible that the observed changes were mediated by the metabolic conversion ofE2 to its quinone derivatives, resulting in mutagenic DNA adduct formation (26-28). The increase in tissue E2 levels alone in the untreated ARO transgenic mice does not seem to have carcinogenic effects. However, through these mechanisms, E metabolism may result in increased DMBA carcinogenicity (29) in the treated ARO transgenic mice. DMBA is a ligand for the aryl hydrocarbon receptor (AhR), a transcription factor that induces the expression of the oxidative P450 enzymes, CYP1-A1 and -B1 (30). DMBA treatment enhances MG AhR and CYP1B1 expression in a rat model system (30). Conversely, AhR is drastically increased in the DMBA-treated ARO transgenic mice as compared to the other mice groups. These studies suggest that E may act as a mitogenic, thus providing an expanded target population for subsequent initiating events.

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