Extracellular matrix remodeling as a regulator of stromal-epithelial interactions during mammary gland development, involution and carcinogenesis

Z. Werb, J. Askenas, A. MacAuley, Jane Wiesen

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

An intact basement membrane is essential for the proper function, differentiation and morphology of many epithelial cells. The disruption or remodeling of the basement membrane occurs during normal development as well as in the disease state. Stromelysin-1 (SL-1), a member of the matrix metalloproteinase (MMP) family, was one of the first proteinases found to be associated with cancer. In this review we describe the role of MMPs in normal mammary gland involution. To examine the importance of basement membrane during development in vivo, we altered the MMP and tissue inhibitor of metalloproteinases (TIMP) balance in mammary gland. Inhibition of MMP synthesis by glucocorticoids or implants or transgenic overexpression of TIMP-1 delays matrix degradation and the involution process after weaning. The mammary glands from transgenic mice that inappropriately express autoactivating isoforms of SL-1 are both functionally and morphologically altered throughout development. Transgenic mammary glands have supernumerary branches, and show precocious development of alveoli that express β-casein expression and undergo unscheduled apoptosis during pregnancy. This is accompanied by progressive development of an altered stroma, which resembles that of a wound site or a tumor, and becomes fibrotic after postweaning involution, and by development of neoplasias. These data suggest that MMPs and disruption of the basement membrane may play key roles in branching morphogenesis of mammary gland, apoptosis, and stromal fibrosis as well as in induction and progression of breast cancer. These observations suggest that SL-1 and other MMPs may be useful targets for therapeutic intervention in cancer.

Original languageEnglish (US)
Pages (from-to)1087-1097
Number of pages11
JournalBrazilian Journal of Medical and Biological Research
Volume29
Issue number9
StatePublished - Sep 1996
Externally publishedYes

Fingerprint

Human Mammary Glands
Matrix Metalloproteinases
extracellular matrix
mammary glands
carcinogenesis
Extracellular Matrix
stromelysin 1
basement membrane
metalloproteinases
Carcinogenesis
Basement Membrane
Matrix Metalloproteinase 3
neoplasms
genetically modified organisms
Neoplasms
apoptosis
Apoptosis
interstitial collagenase
Tissue Inhibitor of Metalloproteinases
Tissue Inhibitor of Metalloproteinase-1

Keywords

  • Apoptosis
  • Extracellular matrix
  • Mammary gland
  • Matrix metalloproteinases
  • Stromal-epithelial interactions
  • Stromelysin-1

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)

Cite this

Extracellular matrix remodeling as a regulator of stromal-epithelial interactions during mammary gland development, involution and carcinogenesis. / Werb, Z.; Askenas, J.; MacAuley, A.; Wiesen, Jane.

In: Brazilian Journal of Medical and Biological Research, Vol. 29, No. 9, 09.1996, p. 1087-1097.

Research output: Contribution to journalArticle

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