Daniel Medina, Ph.D.
Department of Molecular & Cellular Biology
Ph.D., University of California, Berkeley
Breast cancer is the major cancer of women in the United States and will cause over 40,000 deaths in 2003. Although the main risk factors are genetics, age and reproductive history, fully 60 percent of human breast cancers are not defined by these risk factors. Thus, the etiology and underlying mechanisms of breast cancer remain elusive.
Rodent models for breast cancer have been important for elucidating the histopathology, tumor progression, etiological agents, and molecular mechanisms involved in this disease. We are using traditional mouse and rat breast cancer models to investigate fundamental questions regarding the molecular changes involved in tumor development, as well as in hormone-mediated prevention of the disease. In addition, we are developing new mouse models using cre-lox technology that more closely mimic human disease. In the mouse model, we have developed an in vivo-in vitro model where the sequential development of the malignant phenotype is represented in different defined cell populations. These populations are being examined by molecular biological approaches to detect, characterize and define the functional properties of genes uniquely up-regulated or down-regulated at each stage of neoplastic development. Cell cycle genes are differentially expressed in the in vivo-in vitro mouse model in a pattern which shows sequential deregulation of specific genes at different stages of tumor development. Global gene expression methods are being utilized to detect several unique genes up-regulated in the tumorigenic phenotype. The function of TP53, a known tumor suppressor gene, has been examined in a new model where p53 has been deleted from the mammary gland. The role of hormones in genetic instability and tumorigenesis is being examined in this model. The major changes in gene expression as a function of tumor development in our mouse model are illustrated in the figure below.
In a multi-lab collaborative project, the MNU-rat mammary tumor model is being examined to define the endocrinological and growth factor alterations involved in mediating the pregnancy-induced refractory state to carcinogenesis. The mechanisms underlying this event are unresolved.
Medina D and Smith GH. (1999). Chemical carcinogen-induced tumorigenesis in parous, involuted mouse mammary glands. J. Natl. Cancer Inst. 91:967-969.
Lydon JP, Gouging G, Kittrell FS, Medina D and O'Malley BW. (1999). Murine mammary gland carcinogenesis is critically dependent on progesterone receptor function. Cancer Res. 59:4276-4284.
Jerry DJ, Kittrell FS, Kuperwasser C, Laucirica R, Dickinson ES, Bonilla PJ, Butel JS and Medina D. (2000). A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development. Oncogene 19:1052-1058.
Goepfert TM, McCarthy M, Kittrell FS, Stephens C, Ullrich RL, Brinkley BR and Medina D. (2000). Progesterone facilitates chromosome instability (aneuploidy) in p53 null normal mammary epithelial cells. FASEB Journal 14:2221-2229.
Sivaraman L, Conneely OM, Medina D and O'Malley BW (2001). P53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis. Proc. Natl. Acad. Sci. USA 98:12379-12384.
Medina D, et al. (2002) Biological and genetic properties of the p53 null preneoplastic mammary epithelium. FASEB Journal 16:881-883.
Medina D, Kittrell FS, Shepard A, Contreras A, Rosen JM and Lydon J. (2003) Hormone dependence in premalignant mammary progression. Cancer Res. 63:1067-1072.