Matrix Dependent Mechanisms Involved in Tumor Promotion in Initiated Human Mammary Epithelium by Reactive Stroma
Annual summary rept. 1 Jun 2000-31 May 2001
CALIFORNIA UNIV SAN FRANCISCO
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The mammary gland relies on stromal-epithelial interactions for proper development. Tumorigenesis occurs when these signals are misinterpreted. Here we show that stromal matrix metalloproteinases MMPs have distinct roles in mammary gland branching morphogenesis. MMP activity is required for normal mammary gland development since mice treated with a synthetic MMP inhibitor, GM6OOl, have retarded ductal development. Furthermore, 3D cultures of mammary organoids also require MMP activity to branch in response to growth factors, indicating a mammary specific response. We also show that specific MMPs are required for distinct aspects of mammary gland morphogenesis. Specifically, MMF-3 is needed for branching because MMP-3 null mice have significantly fewer branches than controls. However, the ductal length is normal. In contrast, MMP-2 is required for ductal elongation, since the ducts of MMP-2 null mice are retarded in their penetration into the fat pad. However, the branching of the MMP-2 null ducts is normal. MMP-l4 is a known activator of MMP-2 and we show it is highly expressed in front of terminal end buds. Mammary glands deficient in MMP-l4 grown under the kidney capsule of nude mice also have defective ductal morphogenesis. Thus, these stromal enzymes are important, and have distinct roles, in patterning the mammary gland.
- Anatomy and Physiology
- Medicine and Medical Research