Mouse models for breast cancer.

Introduction Recent advances in gene targeting technologies in the mouse have taken us one leap closer to understanding the genetic pathways that operate during normal mammary gland development and tumorigenesis. The possibility to delete or mutate genes specifically in mammary epithelial cells and at predetermined time points permits investigators to analyze the fates of defined cell types in the absence of confounding systemic effects. Gene deletion (knockout) and transgenic mice, both alone and in combination, can be used to address specific questions in developmental and cancer biology. The genetic ablation of steroid (estrogen and progesterone) and peptide (prolactin, epidermal growth factor) hormone receptors and their ligands has provided a deep insight into their function during ductal and alveolar development and has shed light on their redundancy and parallel pathways. Finally, the deletion of transcription factors, including those that mediate peptide hormone signaling, has revealed distinct roles in epithelial cell proliferation, differentiation, and death (for a detailed assessment of genetic approaches to study mammary development, see [1]). Rather than describing individual models (an array of mouse models will be presented in depth in the January 2000 issue of the journal Oncogene), herein I discuss some of the lessons we have learned during the past 15 years from the mice models that are at hand, and the technological hurdles we now encounter. Like in many explorations, the initial concepts, approaches, and tools are rather crude and need to be further developed and refined as new information streams in and new hypotheses are articulated. On the basis of this need I present contemporary approaches that should aid our quest to identify and understand molecular pathways of pathogenesis. Experiments conducted by Philip Leder and coworkers 15 years ago represent a milestone in breast cancer research [2]. They fused the long terminal repeat (LTR) of the mouse mammary tumor virus (MMTV) to the human c-myc proto-oncogene and incorporated this hybrid gene into mice. These transgenic mice expressed the human myc protein in their mammary glands, which resulted in the development of breast tumors [2]. This landmark paper helped to establish an entirely new research arena poised to identify genetic pathways that control breast cancer. After decades of research on tissue culture cells, both federal and private funding agencies saw the opportunity to extend investigations into settings that more closely resembled the human condition. Fifteen years after the study by Leder and coworkers, research by Deng (a former student of Leder) and coworkers set another milestone towards this goal. These investigators succeeded in inactivating the breast cancer gene Brca1 specifically in mammary epithelial cells of mice, and they demonstrated that mammary tumors coincided with genome instability [3]. The distinct lesson learned from these studies was that the wrongful expression of an oncogene and the inactivation of a tumor suppressor gene in mice can cause cancer, just like in humans. However, the myc and Brca1 mice differ in two fundamental aspects from the human situation. In the myc mice oncogene activity occurs as early as puberty, whereas in humans genetic changes leading to cancer may occur later in life. The appearance of tumors in Brca1 conditional mice depends on the loss of both alleles, whereas in humans only one BRCA1 allele is altered (for discussion, see [4]).