Conditional mouse models of breast cancer
Authors: Xiaoling Liu, Patrick Derksen, Bastiaan Evers, Henne Holstege, Hanneke Van der Gulden, Paul Krimpenfort, Anton Berns, Jos Jonkers
Journal: Cancer Research (2005)

1076   The sequence of causative events in human cancers is obscured by the multitude of genetic alterations that have occurred by the time tumors are detected. It is therefore of importance to design model systems in which the importance of the various mutations can be assessed. To establish mouse models of breast cancer, we have used the Cre/ loxP  system for time- and tissue-restricted switching of multiple tumor suppressor genes within cells  in vivo . This technology enables the induction of defined tumors within a narrow time window, and the correlation of specific genetic lesions with phenotypic characteristics of the tumor. We have generated a mouse breast cancer model based upon tissue-specific p53 inactivation in mammary epithelial cells. To this end, we generated conditional  p53  flox  mice and crossed these animals with  K14cre  transgenic mice in which Cre expression in skin and mammary gland epithelium is driven by the cytokeratin-14 promoter. Indeed, the  K14cre ; p53  flox/flox  females developed, in addition to skin tumors, mammary gland adenocarcinomas with a median latency of approximately 330 days. To establish mouse models for BRCA1- and BRCA2-associated breast cancer, we have generated conditional  Brca1  flox  and  Brca2  flox  mice, and cross-bred both strains with our  K14cre ; p53  flox/flox  mammary tumor model. Using the various compound mutant strains, we were able to show that Brca1/2 and p53 loss-of-function effectively collaborate in skin- and mammary tumorigenesis, indicating a pivotal role of the p53 pathway in BRCA1- or BRCA2-associated breast cancer. To identify specific differences between the Brca1 and Brca2 tumors, we have performed pair-wise comparisons of the molecular profiles from the Brca1 and Brca2 groups. We have also compared the molecular profiles of the Brca1 and Brca2 tumors with the profiles of the p53 control tumors to identify alterations that are specific for BRCA1- or BRCA2-associated breast cancer. Ultimately, such a comparative analysis may identify novel oncogenic mutations that cooperate with BRCA1- and/or BRCA2-loss in mammary tumorigenesis. As none of the mammary tumors from our  K14cre ; p53  flox/flox  model show local invasion or metastatic capacity, this model is therefore suitable for investigating phenotypic consequences of additional (conditional) mutations in genes involved in tumor progression and metastasis. A strong candidate is the cell adhesion molecule E-cadherin, of which decreased expression is associated with poor prognosis in breast cancer. We have introduced conditional E-cadherin alleles into our  p53  mammary tumor model via crossbreeding. Our data indicate an effective collaboration between E-cadherin loss and p53 inactivation in skin and mammary tumorigenesis. Histopathologic analysis of the resulting tumors indicates that loss of E-cadherin results in highly metastatic malignancies, and in a switch from ductal to lobular mammary carcinomas, reminiscent of the human condition.