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Title: Expression of Autoactivated Stromelysin-1 in Mammary Glands of Transgenic Mice Leads to a Reactive Stroma During Early Development

Abstract

Extracellular matrix and extracellular matrix-degrading matrix metalloproteinases play a key role in interactions between the epithelium and the mesenchyme during mammary gland development and disease. In patients with breast cancer, the mammary mesenchyme undergoes a stromal reaction, the etiology of which is unknown. We previously showed that targeting of an autoactivating mutant of the matrix metalloproteinase stromelysin-1 to mammary epithelia of transgenic mice resulted in reduced mammary function during pregnancy and development of preneoplastic and neoplastic lesions. Here we examine the cascade of alterations before breast tumor formation in the mammary gland stroma once the expression of the stromelysin-1 transgene commences. Beginning in postpubertal virgin animals, low levels of transgene expression in mammary epithelia led to increased expression of endogenous stromelysin-1 in stromal fibroblasts and up-regulation of other matrix metalloproteinases, without basement membrane disruption. These changes were accompanied by the progressive development of a compensatory reactive stroma, characterized by increased collagen content and vascularization in glands from virgin mice. This remodeling of the gland affected epithelial-mesenchymal communication as indicated by inappropriate expression of tenascin-C starting by day 6 of pregnancy. This, together with increased transgene expression, led to basement membrane disruption starting by day 15 of pregnancy. We propose thatmore » the highly reactive stroma provides a prelude to breast epithelial tumors observed in these animals. Epithelial development depends on an exquisite series of inductive and instructive interactions between the differentiating epithelium and the mesenchymal (stromal) compartment. The epithelium, which consists of luminal and myoepithelial cells, is separated from the stroma by a basement membrane (BM), which plays a central role in mammary gland homeostasis and gene expression. In vivo, stromal cells produce fibronectin, collagens, proteoglycans, and some components of the BM, as well as a number of proteinases that can effectively degrade BM constituents. Stromal and epithelial cells of the mammary gland interact to regulate BM synthesis and degradation and, thus, mammary function. Matrix metalloproteinases (MMPs) are extracellular matrix (ECM)-degrading enzymes involved in mammary gland morphogenesis and involution. During late pregnancy and lactation, when the gland becomes fully functional, the expression of MMPs is low however, during involution, when the gland loses function and is remodeled, synthesis of ECM-degrading proteinases increases dramatically.11 Disturbance of the balance between MMPs and MMP inhibitors leads to either unscheduled involution or prolonged lactation. Mammary glands of virgin mice expressing an autoactivating stromelysin-1 (SL-1) transgene display supernumerary branches and precocious alveolar development, accompanied by the synthesis of {beta}-casein at levels found normally only during early pregnancy. During late pregnancy, increased expression of the SL-1 transgene leads to a reduction in expression of pregnancy-specific genes. Later in life, some SL-1 transgenic mice develop hyperplastic, dysplastic, and ductal carcinoma in situ-like lesions, as well as malignant tumors. Little is known about the sequence of changes that occurs before formation of an overt reactive stroma in breast cancer. In the present study, we address the question of whether and how the stromal compartment is altered as a consequence of inappropriate SL-1 transgene expression in the epithelium.« less

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
Life Sciences Division
OSTI Identifier:
993487
Report Number(s):
LBNL-42034
Journal ID: ISSN 0002-9440; AJPAA4; TRN: US201023%%491
DOE Contract Number:  
DE-AC02-05CH11231
Resource Type:
Journal Article
Journal Name:
American Journal of Pathology
Additional Journal Information:
Journal Volume: 153; Journal Issue: 2; Related Information: Journal Publication Date: 8/1/1998; Journal ID: ISSN 0002-9440
Country of Publication:
United States
Language:
English
Subject:
99 GENERAL AND MISCELLANEOUS; CARCINOMAS; COLLAGEN; ENZYMES; EPITHELIUM; ETIOLOGY; FIBROBLASTS; GENES; GLANDS; HOMEOSTASIS; LACTATION; MAMMARY GLANDS; MEMBRANES; MICE; MORPHOGENESIS; NEOPLASMS; PATIENTS; PHENOBARBITAL; PREGNANCY; SYNTHESIS; TRANSGENIC MICE

Citation Formats

Thomasset, N., Lochter, A., Sympson, C.J., Lund, L.R., Williams, D.R., Behrendtsen, O., Werb, Z., and Bissell, M.J. Expression of Autoactivated Stromelysin-1 in Mammary Glands of Transgenic Mice Leads to a Reactive Stroma During Early Development. United States: N. p., 1998. Web. doi:10.1016/S0002-9440(10)65589-7.
Thomasset, N., Lochter, A., Sympson, C.J., Lund, L.R., Williams, D.R., Behrendtsen, O., Werb, Z., & Bissell, M.J. Expression of Autoactivated Stromelysin-1 in Mammary Glands of Transgenic Mice Leads to a Reactive Stroma During Early Development. United States. doi:10.1016/S0002-9440(10)65589-7.
Thomasset, N., Lochter, A., Sympson, C.J., Lund, L.R., Williams, D.R., Behrendtsen, O., Werb, Z., and Bissell, M.J. Fri . "Expression of Autoactivated Stromelysin-1 in Mammary Glands of Transgenic Mice Leads to a Reactive Stroma During Early Development". United States. doi:10.1016/S0002-9440(10)65589-7. https://www.osti.gov/servlets/purl/993487.
@article{osti_993487,
title = {Expression of Autoactivated Stromelysin-1 in Mammary Glands of Transgenic Mice Leads to a Reactive Stroma During Early Development},
author = {Thomasset, N. and Lochter, A. and Sympson, C.J. and Lund, L.R. and Williams, D.R. and Behrendtsen, O. and Werb, Z. and Bissell, M.J.},
abstractNote = {Extracellular matrix and extracellular matrix-degrading matrix metalloproteinases play a key role in interactions between the epithelium and the mesenchyme during mammary gland development and disease. In patients with breast cancer, the mammary mesenchyme undergoes a stromal reaction, the etiology of which is unknown. We previously showed that targeting of an autoactivating mutant of the matrix metalloproteinase stromelysin-1 to mammary epithelia of transgenic mice resulted in reduced mammary function during pregnancy and development of preneoplastic and neoplastic lesions. Here we examine the cascade of alterations before breast tumor formation in the mammary gland stroma once the expression of the stromelysin-1 transgene commences. Beginning in postpubertal virgin animals, low levels of transgene expression in mammary epithelia led to increased expression of endogenous stromelysin-1 in stromal fibroblasts and up-regulation of other matrix metalloproteinases, without basement membrane disruption. These changes were accompanied by the progressive development of a compensatory reactive stroma, characterized by increased collagen content and vascularization in glands from virgin mice. This remodeling of the gland affected epithelial-mesenchymal communication as indicated by inappropriate expression of tenascin-C starting by day 6 of pregnancy. This, together with increased transgene expression, led to basement membrane disruption starting by day 15 of pregnancy. We propose that the highly reactive stroma provides a prelude to breast epithelial tumors observed in these animals. Epithelial development depends on an exquisite series of inductive and instructive interactions between the differentiating epithelium and the mesenchymal (stromal) compartment. The epithelium, which consists of luminal and myoepithelial cells, is separated from the stroma by a basement membrane (BM), which plays a central role in mammary gland homeostasis and gene expression. In vivo, stromal cells produce fibronectin, collagens, proteoglycans, and some components of the BM, as well as a number of proteinases that can effectively degrade BM constituents. Stromal and epithelial cells of the mammary gland interact to regulate BM synthesis and degradation and, thus, mammary function. Matrix metalloproteinases (MMPs) are extracellular matrix (ECM)-degrading enzymes involved in mammary gland morphogenesis and involution. During late pregnancy and lactation, when the gland becomes fully functional, the expression of MMPs is low however, during involution, when the gland loses function and is remodeled, synthesis of ECM-degrading proteinases increases dramatically.11 Disturbance of the balance between MMPs and MMP inhibitors leads to either unscheduled involution or prolonged lactation. Mammary glands of virgin mice expressing an autoactivating stromelysin-1 (SL-1) transgene display supernumerary branches and precocious alveolar development, accompanied by the synthesis of {beta}-casein at levels found normally only during early pregnancy. During late pregnancy, increased expression of the SL-1 transgene leads to a reduction in expression of pregnancy-specific genes. Later in life, some SL-1 transgenic mice develop hyperplastic, dysplastic, and ductal carcinoma in situ-like lesions, as well as malignant tumors. Little is known about the sequence of changes that occurs before formation of an overt reactive stroma in breast cancer. In the present study, we address the question of whether and how the stromal compartment is altered as a consequence of inappropriate SL-1 transgene expression in the epithelium.},
doi = {10.1016/S0002-9440(10)65589-7},
journal = {American Journal of Pathology},
issn = {0002-9440},
number = 2,
volume = 153,
place = {United States},
year = {1998},
month = {4}
}