Genetic alterations in the development of mammary and prostate cancer in the C3(1)/Tag transgenic mouse model.

We have generated a transgenic mouse model in which female mice develop ductal mammary adenocarcinomas and male mice develop prostatic adenocarcinomas by using a transgene containing the hormone-responsive rat prostatic steroid binding protein 5' flanking region C3(1) fused to the simian virus 40 (SV40) large T antigen. We have identified some genetic alterations during mammary and prostate tumor progression: (i) p53 is functionally inactivated during mammary cancer development without p53 mutations; (ii) Alterations in apoptosis during mammary tumor progression are p53 and bcl-2 independent; (iii) Ha-ras mutations occur early in the development of prostate cancer. This unique animal model offers the opportunity to study multistep tumorigenesis in these organs.

p53-independent apoptosis during mammary tumor progression in C3(1)/SV40 large T antigen transgenic mice: suppression of apoptosis during the transition from preneoplasia to carcinoma.

Alterations in apoptosis and associated mechanisms during mammary tumor progression were investigated in transgenic mice expressing the SV40 large T antigen (T(AG)) driven by the rat prostatic steroid-binding protein C3(1) 5'-flanking region. Apoptosis levels, assessed by in situ end labeling, were low in normal mammary epithelial cells, highest in atypical hyperplasias (preneoplastic lesions), and less pronounced in adenocarcinomas. Preneoplastic cells maintain the ability to undergo apoptosis as a mechanism of tumor growth suppression, but this critical control of apoptosis is lost as these lesions progress to carcinomas. These alterations in apoptosis occur during mammary tumor progression in mice containing wild-type p53+/+ genotype as well as in mice with the p53-/- genotype. Thus, apoptosis in this tumor model occurs through a p53-independent mechanism. Because other studies have demonstrated p53-dependent apoptosis in T(AG)-induced choroid plexus tumors of transgenic mice, we propose that the role of p53 in apoptosis may be tissue-specific. In addition, bcl-2 protein was not expressed in any mammary lesions. SV40 T(AG) expression, which correlated with the nuclear p53 protein at all stages of tumor progression, was low in normal mammary epithelial cells, moderately high in atypical hyperplasias, and strongly expressed in adenocarcinomas. No p53 mutations were found at any stage of mammary adenocarcinoma development, suggesting that tumor progression does not require a dominantly acting p53 mutation in this transgenic model. p2l(Waf1/Cip1), a cyclin-dependent kinase inhibitor, was expressed in normal mammary tissue but was not detected in the mammary carcinomas, despite high nuclear accumulation of wild-type p53 protein, suggesting functional loss of p53 due to binding of SV40 T(AG), to p53. These findings suggest that suppression of apoptosis during the transition from atypical hyperplasia to adenocarcinoma appears to be a critical event for mammary cancer development in C3(1)/T(AG) transgenic mice and occurs by p53- and bcl-2-independent pathways.

Specific pathogen-free BALB/cAn mice are refractory to plasmacytoma induction by pristane.

Forty to sixty percent of conventionally (CON) raised BALB/cAnPt (BALB/c) mice develop plasmacytomas (PCT) when injected with three 0.5 ml i.p. injections of pristane. When CON-BALB/c mice were converted to specific pathogen free (SPF) status by foster nursing caesarean delivered term mice on C3H/HeN SPF mothers and maintained under strict SPF conditions, less than 5% of the mice developed pristane-induced PCT. FACS analysis of the cellular composition of oil granulomatous tissue revealed a dramatic influx of CD4+ cells in CON mice that was significantly reduced in SPF mice. Moreover, while both CON and SPF mice had similar patterns of gut flora colonization, only CON-BALB/c mice had occasional circulating antibodies to mouse hepatitis virus and Sendai viruses. Maintenance in strict SPF conditions, therefore, results in a prolonged state of relative Ag deprivation and a failure to continuously activate new T and B cell populations. The results suggest that PCT formation depends on exogenous antigenic stimulation and that the presence of minimal gut flora is insufficient to render these mice susceptible to PCT induction.

Selenium accumulation and elimination in mallards.

Selenium accumulation and loss were measured in adult mallards (Anas platyrhynchos) fed selenomethionine during two experiments. In Experiment 1, both sexes were fed a diet containing 10 ppm selenium for 6 weeks, followed by 6 weeks on untreated feed. Selenium accumulation in liver and muscle of females was described by C = A(1-e-bt). Concentrations of selenium were predicted to reach 95% of equilibrium faster in liver (7.8 days) than in muscle (81 days). The loss of selenium from liver and muscle of females was described by the exponential loss rate equation: C = Ae-bt, with half-times of 18.7 and 30.1 days, respectively. Males reached similar levels of selenium in liver and breast muscle as females and declined to similar levels once selenium treatment ended. In Experiment 2, females were fed increasing levels of selenium until some died. Survivors were switched to an untreated diet and selenium was measured in blood, liver, and breast muscle over 64 days. The same equation as in Experiment 1, C = Ae-bt, was used to describe the loss of selenium from blood and muscle. Half-times were 9.8 and 23.9 days, respectively. For liver, the equation C = A1e-b1t + A2e-b2t was used. Selenium initially decreased in liver by one-half in 3.3 days, with subsequent half-times of 3.9, 6.0, and 45.1 days.