The 5'¯anking region of the C3(1) component of the rat prostate steroid binding protein (PSBP) has been used to successfully target the expression of the SV40 large Tantigen (Tag) to the epithelium of both the mammary and prostate glands resulting in models of mammary and prostate cancers which histologically resemble the human diseases. Atypia of the mammary ductal epithelium develops at about 8 weeks of age, progressing to mammary intraepithelial neoplasia (resembling human ductal carcinoma in situ [DCIS]) at about 12 weeks of age with the development of invasive carcinomas at about 16 weeks of age in 100% of female mice. The carcinomas share features to what has been classi®ed in human breast cancer as in®ltrating ductal carcinomas. All FVB/N female mice carrying the transgene develop mammary cancer with about a 15% incidence of lung metastases. Approximately 10% of older male mice develop anaplastic mammary carcinomas. Unlike many other transgenic models in which hormones and pregnancy are used to induce a mammary phenotype, C3(1)/Tag mice develop mammary tumors in the mammary epithelium of virgin animals without hormone supplementation or pregnancy. Although mammary tumor development appears hormone-responsive at early stages, invasive carcinomas are hormone-independent, which corresponds to the loss of estrogen receptor-a expression during tumor progression. Molecular and biologic factors related to mammary tumor progression can be studied in this model since lesions evolve over a predictable time course. Genomic alterations have been identi®ed during tumor progression, including an ampli®cation of the distal portion of chromosome 6 containing ki-ras and loss of heterozygosity (LOH) in other chromosomal regions. We have demonstrated that stage speci®c alterations in the expression of genes which are critical regulators of the cell cycle and apoptosis are functionally important in vivo. C3(1)/Tag mice appear useful for testing particular therapies since growth of the mammary tumors can be reduced using chemopreventive agents, cytokines, and an anti-angiogenesis agent.

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Despite a continuing debate about the existence of cancer stem cells (CSCs), recent discoveries have provided further support for their existence and their roles in drug resistance, cancer recurrence and metastasis. CSC characteristics, such as self-renewal and tumour initiation, and supporting cellular processes, particularly the epithelial-to-mesenchymal transition, are attracting a great deal of attention from cancer researchers as they offer opportunities for discovering novel therapeutic targets for future drug development. However, the identification of potential CSC targets presents clear obstacles due to a lack of truly specific CSC markers and the reality of CSC plasticity, making this task a significant challenge. Agents that target developmental signalling pathways, such as Notch, Wnt and Hedgehog, are now in clinical trials whilst alternative approaches including immune-based therapies and microRNA-mediated pathway inhibitors are producing promising pre-clinical results. Here, we discuss the contribution of CSCs to cancer metastasis and the scope of opportunities for therapeutic intervention. In particular, we consider CSC-targeting agents for which there is experimental evidence of anti-metastatic properties and which may have potential to eventually limit relapse and impede metastasis in patients.

We explored the risk factors for gallbladder cancer and explanations for its sharp and constant incidence increase in Chile since the 1970s. We compared 114 consecutive patients with verified gallbladder cancer, diagnosed 1992-1995, to 114 matched hospital patients with gallstones, using conditional logistic regression analysis. Low education showed a nonsignificant positive relationship with gallbladder cancer [odds ratio (OR) ‫؍‬ 2.3, 95% confidence interval (CI) 0.8 -6.2], and low socioeconomic level showed a significant relationship (OR ‫؍‬ 5.0, 95% CI 1.5-17.3). A very long history of gallstone disease was significantly more prevalent among cases (OR ‫؍‬ 11.0, 95% CI 1.4 -85.2). Significant red chili pepper consumption was observed in gallbladder cancer patients (OR ‫؍‬ 2.9, 95% CI 1.6 -5.2). Low intake of both fresh fruit and sugar as soft drinks was associated with gallbladder cancer, with ORs of 6.4 (95% CI 1.4 -30.3) and 3.6 (95% CI 1.3-10.1), respectively. Multivariate analysis kept only a very low socioeconomic status and red chili pepper consumption as significant independent risk factors for gallbladder cancer, ORs of 6.3 (95% CI 1.7-23.0) and 3.2 (95% CI 1.7-5.9). Longstanding gallstone cases were removed from the multivariate model because all were in the low and very low socioeconomic groups, reinforcing the association. Patients with gallbladder cancer differed from matched controls by exhibiting lower socioeconomic levels, having a much longer history of gallstone disease and presenting a dietary pattern characterized by high red chili pepper consumption and low fresh fruit intake.