Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1

Abstract

An intact basement membrane (BM) is essential for the proper function, differentiation and morphology of many epithelial cells. The disruption or loss of this BM occurs during normal development as well as in the disease state. To examine the importance of BM during mammary gland development in vivo, we generated transgenic mice that inappropriately express autoactivating isoforms of the matrix metalloproteinase stromelysin-1. The mammary glands from these mice are both functionally and morphologically altered throughout development. We have now documented a dramatic incidence of breast tumors in several independent lines of these mice. These data suggest that overexpression of stromelysin-1 and disruption of the BM may be a key step in the multi-step process of breast cancer.

Figure 1

Phenotype of normal and transgenic mammary glands in virgin mice. Whole-mount carmine-stained glands from normal CD-1 mice: 70-day virgin (A), 50-day virgin transgenic (B), and 70-day virgin transgenic (C). The 70-day transgenic gland (C) is highly branched with prominent alveolar structures and closely resembles a normal 9–12-day pregnant gland. An intermediate phenotype can be captured at day 50 of virgin transgenic development (B). The dark-staining oval structures are the lymph nodes. Photographs are 6 × magnification. See Sympson et al, 1994, for details.

Figure 2

Morphology of mammary glands from normal and SL-1-overexpressing transgenic mice. Whole-mount carmine-stained glands from normal (A) and transgenic tumor-bearing (B) mice and the corresponding hematoxylin-eosin-stained cross sections, C and D, respectively. The arrow in panel B corresponds to the enlarged cross-section in panel D, which demonstrates an encapsulated adenocarcinoma. Both glands are the thoracic (nos 2/3) taken 4 months after the first lactation. Photographs in A and B are 6 × magnification and C and D are 40 × magnification.