Mammary epithelial cell transformation: insights from cell culture and mouse models

More than 80% of adult human cancers are carcinomas, tumors originating from malignant transformation of epithelial cells. However, much of our understanding of oncogenic transformation comes from fibroblast transformation systems. Breast cancer is the second leading cause of cancer-related deaths among women in the USA [1]. The vast majority of breast cancers are carcinomas that originate from cells lining the milk-forming ducts of the mammary gland (for review [2]). Deliberate transformation of these cells provides a practical window into human epithelial oncogenesis. Malignant transformation represents a complex multistep process in which genetic, environmental, and dietary factors together are thought to alter critical cell growth regulatory pathways resulting in uncontrolled proliferation, which is a hallmark of tumorigenesis [3,4]. Understanding the nature of these cellular pathways is of central importance in cancer biology.The growth of normal human mammary epithelial cells (HMECs), which include luminal, myoepithelial and/or basal cells (described below), is tightly controlled. These cells grow for a finite life span and eventually senesce (for review [5-7]). Both cell culture and mouse models have provided evidence that essential initial steps in tumorigenesis involve the loss of senescence checkpoints and immortalization, which allow a cell to grow indefinitely and to go through further oncogenic steps, resulting in fully malignant behavior. In addition, cell culture model systems have identified a number of genes whose alterations are involved in HMEC immortalization and thereby have provided significant insights into the biology of early breast cancer [5,7,8]. Use of oncogene combinations has allowed researchers to create cell culture models of full HMEC transformation, thereby illuminating the process of breast cancer progression [9-11]. Additional insights have come from mouse models, using transgenic overexpression of oncogenesis-promoting genes and