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 in-teractions 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. (Am J Pathol 1998, 153:457-467) Epithelial development depends on an exquisite series of inductive and instructive interactions between the differentiating epithelium and the mesenchymal (stromal) compartment.

Putting tumours in context

“…Here, the causative mechanism seems to be that SL-1 -expressed ectopically at low levels in the epithelial cells -is subsequently produced at much higher levels by the stromal fibroblasts 44 , showing that a moderate disruption contributes to a selfsustaining tumorigenic state. Similar reciprocal feedback mechanisms have been observed in transgenic mice with altered expression of MMP-7 (REF.…”

“…In transgenic mice that express SL-1 in mammary luminal epithelial cells, the mammary glands show morphogenesis defects and contain pre-neoplastic lesions 44,53,54 that eventually lead to full malignancies 50,54 . Here, the causative mechanism seems to be that SL-1 -expressed ectopically at low levels in the epithelial cells -is subsequently produced at much higher levels by the stromal fibroblasts 44 Macrophage migration inhibitory factor (MIF) is another immunomodulator that is associated with tumour progression.…”

“…Here, the causative mechanism seems to be that SL-1 -expressed ectopically at low levels in the epithelial cells -is subsequently produced at much higher levels by the stromal fibroblasts 44 Macrophage migration inhibitory factor (MIF) is another immunomodulator that is associated with tumour progression. This cytokine has been shown to be overexpressed by tumour cells 77 , contributing to neoangiogenesis and to epithelial cell proliferation 77 , as well as suppressing immune surveillance 78 .…”

“…Moreover, studies of a subset of inherited cancer-susceptibility syndromes 42,43 also indicate that alterations in stromal cells can contribute to tumorigenesis. So, aberrations in stroma can both precede and stimulate the development of epithelial cancers 44,45 .…”

“…Cellular context determines the response of mammary epithelial cells to SL-1 treatment: when grown in basement-membrane gels, mammary epithelial cells undergo growth arrest and become functionally differentiated; subsequent treatment of these cells with SL-1 causes apoptosis 52 . However, when cultured on two-dimensional matrices and allowed to continuously proliferate, mammary epithelial cells react to treatment with SL-1 by undergoing an epithelial-mesenchymal transition and becoming tumorigenic 50 .In transgenic mice that express SL-1 in mammary luminal epithelial cells, the mammary glands show morphogenesis defects and contain pre-neoplastic lesions 44,53,54 that eventually lead to full malignancies 50,54 . Here, the causative mechanism seems to be that SL-1 -expressed ectopically at low levels in the epithelial cells -is subsequently produced at much higher levels by the stromal fibroblasts 44 Macrophage migration inhibitory factor (MIF) is another immunomodulator that is associated with tumour progression.…”