Genetically engineered mice as experimental tools to dissect the critical events in breast cancer

Abstract

Elucidating the mechanism of pathogenesis of breast cancer has greatly benefited from breakthrough advances in both genetically engineered mouse (GEM) models and xenograft transplantation technologies. The vast array of breast cancer mouse models currently available is testimony to the complexity of mammary tumorigenesis and attempts by investigators to accurately portray the heterogeneity and intricacies of this disease. Distinct molecular changes that drive various aspects of tumorigenesis, such as alterations in tumor cell proliferation and apoptosis, invasion and metastasis, angiogenesis, and drug resistance have been evaluated using the currently available GEM breast cancer models. GEM breast cancer models are also being exploited to evaluate and validate the efficacy of novel therapeutics, vaccines, and imaging modalities for potential use in the clinic. This review provides a synopsis of the various GEM models that are expanding our knowledge of the nuances of breast cancer development and progression and can be instrumental in the development of novel prevention and therapeutic approaches for this disease.

Keywords: Breast cancer; Genetically engineered mouse (GEM) models; Transgenic animals.

Figure 8.1. Schematic of embryonic mammary gland development in mice

(A) Cross-sectional view through the trunk of the mouse during mammary gland development. The milk line (orange) is formed by a slight thickening and stratification of the ectoderm (gray) at around embryonic day 10 (E10). The milk line breaks up into individual placodes (orange) and condensation of the underlying mammary mesenchyme (blue) begins on E11.5. Placodes sink deeper into the dermis and the mammary mesenchyme is organized in concentric layers around the mammary bud (orange) over the next few days. Proliferation of the mammary epithelium (orange) begins at the tip and the primary sprout pushes through the mammary mesenchyme toward the fat pad (green) starting on day E15.5. The elongating duct grows into the fat pad and branches into a small ductal system on E18.5. Cells of the mammary mesenchyme form the nipple consisting of specialized epidermal cells (purple). (B) Schematic of the position of the milk line, placodes, and mammary buds along the lateral body wall of early mouse embryos. Reprinted with permission from MacMillan Publishers Ltd: Nature Reviews Genetics (Robinson, 2007), copyright 2007.

Figure 8.2. The biology of breast cancer

(a) Breast cancer is a multifaceted disease that is genetically and genomically heterogenous. The normal breast terminal ductal lobular unit (TDLU) is comprised of lobules and ducts that consist of bilayered epithelium of luminal and myoepithelial cells. Characterized by abnormal cells within the duct or lobule, atypical ductal hyperplasia (ADH) is a premalignant lesion. ADH is thought to be followed by ductal carcinoma in situ (DCIS), a noninvasive lesion with abnormal cells. Some of the noninvasive DCIS lesions might eventually give rise to invasive breast cancer (IBC). Finally cells that have gained invasive capabilities might metastasis to a distant area in the body. In breast cancer, the primary site of metastasis (MET) is the lymph nodes. (B) Schematic of the progression of breast cancer. Various factors play a role in the transformation of breast epithelial cells to eventually give rise to metastatic breast cancer. This multistep process involves loss of control of proliferation, gain in survival abilities, increased migration, and aberrant tumor–stromal cell interactions that facilitate transformation. Cells must invade through the basement membrane, intravasate into the blood circulation, survive, extravasate from the blood circulation, and establish a new tumor at a distant site in the body, for metastasis to develop. Reprinted with permission from Macmillan Publishers Ltd: Nature Reviews Cancer (Vargo-Gogola & Rosen, 2007), copyright 2007.

Figure 8.3. Applications of transgenic animals in the study of breast cancer

Transgenic animals have greatly advanced our understanding of the biology of breast cancer. They have been invaluable tools in evaluating the role of single or multiple transgenes in the progression of breast cancer and evaluating the impact of factors that might influence the initiation and/or progression of breast cancer. Of particular significance, transgenic animals have been used to evaluate the role of novel therapeutics to target breast cancer, to evaluate novel imaging techniques, and to evaluate the efficacy of newly developed vaccines against breast cancer.