Claudia Lanari

The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

More than 60% of all breast neoplasias are ductal carcinomas expressing estrogen (ER) and progesterone receptors (PR). By contrast, most of the spontaneous, chemically or mouse mammary tumor virus induced tumors, as well as tumors arising in genetically modified mice do not express hormone receptors. We developed a model of breast cancer in which the administration of medroxyprogesterone acetate to BALB/c female mice induces mammary ductal carcinomas with a mean latency of 52 weeks and an incidence of about 80%. These tumors are hormone-dependent (HD), metastatic, express both ER and PR, and are maintained by syngeneic transplants. The model has been further refined to include mammary carcinomas that evolve through different stages of hormone dependence, as well as several hormone-responsive cell lines. In this review, we describe the main features of this tumor model, highlighting the role of PR as a trigger of key signaling pathways mediating tumor growth. In addition, we discuss the relevance of this model in comparison with other presently used breast cancer models pointing out its advantages and limitations and how, this model may be suitable to unravel key questions in breast cancer.

FGFR3 Down-Regulation is Involved in bacillus Calmette-Guérin Induced Bladder Tumor Growth Inhibition

PURPOSE Bacillus Calmette-Guérin is the standard treatment for patients with nonmuscle invasive high histological grade bladder cancer. Previously we found that bacillus Calmette-Guérin induces murine bladder cancer MB49 cell death in vitro and in vivo, generating tissue remodeling, which involves the release of fibroblast growth factor (FGF)-2. MATERIALS AND METHODS We studied the effect of bacillus Calmette-Guérin treatment on FGF-2 and FGF receptor (FGFR) expression in bladder cancer. RESULTS In vitro FGF-2 increased MB49 cell proliferation but did not reverse bacillus Calmette-Guérin induced cell death. Increased FGF-2 expression was detected after bacillus Calmette-Guérin treatment. Moreover MB49 cells expressed high FGFR3 levels, which decreased after treatment. Similar results were observed in human T24 bladder cancer cells. In vivo MB49 tumors expressed higher FGFR3 levels than normal urothelium. Tumor FGFR3 decreased after treatment and correlated with tumor growth inhibition in response to bacillus Calmette-Guérin. In a pilot bioassay using 11 human bladder tumors treated ex vivo with bacillus Calmette-Guérin we found a subgroup of 41% of patients in whom FGFR3 was decreased after treatment. CONCLUSIONS Based on bladder cancer murine model results we infer that down-regulation of FGFR3 is a predictive marker of a good response to bacillus Calmette-Guérin therapy. The decrease in FGFR3 in response to bacillus Calmette-Guérin occurred not only in a murine model but also in a human bladder cancer cell line and in some patient samples. More patients and increased followup are needed to establish the predictive role of FGFR3 as a marker in human bladder cancer.

Pathogenesis of Ductal and Lobular Progestin-Induced Mammary Carcinomas in BALB/c Mice

Several years ago, we demonstrated that medroxyprogesterone acetate (MPA)- induced mammary adenocarcinomas in female BALB/c mice with an incidence close to 80% and a mean latency of around 13 months (1). These tumors were mostly ductal, progestin-dependent (PD) adenocarcinomas with high levels of estrogen and progesterone receptors (ER and PR) (2). We later found that progesterone (P) also induced mammary carcinomas, but this time the tumors were mostly lobular, progestin-independent (PI) adenocarcinomas with lower levels of ER and PR (3). There was a constant correlation between progestin dependence and morphology, that is, lobular carcinomas were always PI and ductal carcinomas PD (3). To extend this study further, we designed a model of co-carcinogenesis using medroxyprogesterone (MPA) with N-methyl N-nitrosourea (MNU) in BALB/c mice. We obtained a high incidence of mammary adenocarcinomas similar to the hormone-induced lobular tumors, and showed that MPA can act as a potent promoter.