Premalignant and Malignant Mammary Lesions Induced by MMTV and Chemical Carcinogens

This article reviews the types of mammary premalignant and malignant lesions induced in the mouse mammary gland after exposure to MMTV and chemical carcinogens. There are different morphological types of hyperplastic lesions in the mouse mammary gland. These lesions are designated as alveolar hyperplasia (HAN), ductal hyperplasia (DH), and cystic lesions; both non-keratinized and keratinized. The HAN and DH have been demonstrated to be precursors to invasive lesions. The HAN as a group tend to be ovarian-hormone independent for growth and transformation, mammary fat pad site-dependent for growth, possess unlimited replication potential (i.e., immortal), are at increased risk for progression to cancer, and are genetically stable. Serial transplantation demonstrates that any given stage of hyperplasia can progress to the next stage, sometimes rapidly and sometimes slowly. Multiple growth factor pathways are deregulated early in the development of HAN depending on etiology of the HAN. One general conclusion that emerges from such studies of HAN induced by different etiologies is that the early stages of premalignancy are a result of defects in cell cycle regulation with subsequent alterations playing a role in the acquisition of invasive phenotype. The predominant lesion induced by chemical carcinogens is the ductal hyperplasia (DH). Although DH show many of the essential biological alterations seen in HAN, they also exhibit a higher frequency of hormone-dependence and genetic instability, thus the DH appearing in chemical carcinogen treated mice and in transgenic mice mimic the histological, biological and genetic properties seen in human premalignant lesions more faithfully than do the HAN. The mammary tumors that arise from both general classes of premalignant lesions are very heterogeneous and exhibit different potentials for metastasis. The cell and molecular biology of metastasis represents an understudied area, in part because of the absence of suitable models to study the metastatic process. Newer transgenic mouse models provide a renewed opportunity to engage in the study of the mechanisms and processes underlying mammary metastasis.