The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis

M D Sternlicht ¹, A Lochter , C J Sympson

⁰Department of Anatomy, University of California, San Francisco 94143-0452, USA. sternli@itsa.ucsf.edu

Cell +

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July 31, 1999

View abstract on PubMed

Summary

Matrix metalloproteinase 3 (MMP3/Str1) drives mammary tumor initiation and invasion. Once formed, tumors become independent of MMP3/Str1, highlighting its role in neoplastic risk.

Area Of Science

Oncology
Molecular Biology
Cancer Research

Background

Matrix metalloproteinases (MMPs) are upregulated in cancer stroma, promoting invasion and metastasis.
MMP3, also known as stromelysin-1 (Str1), is implicated in epithelial cancer progression.

Purpose Of The Study

To investigate the role of MMP3/Str1 in mammary tumor initiation, invasion, and neoplastic risk.
To determine if Str1 expression influences the development of premalignant and malignant lesions in vivo.

Main Methods

Utilized tetracycline-regulated expression of MMP3/Str1 in phenotypically normal mammary epithelial cells in vivo.
Generated transgenic mice with mammary gland-specific Str1 expression.
Assessed tumor formation, invasiveness, and genomic changes.
Investigated the effect of TIMP1 coexpression on Str1-induced changes.

Main Results

MMP3/Str1 expression induced invasive, mesenchymal-like tumors from normal mammary epithelial cells.
Tumors became independent of continued Str1 expression after initiation.
Str1 promoted spontaneous premalignant changes and malignant conversion in mouse mammary glands.
Coexpression of TIMP1 blocked Str1-induced premalignant and malignant lesions.
Lesions exhibited unique genomic alterations compared to other murine models.

Conclusions

MMP3/Str1 plays a critical role in initiating mammary tumors and altering neoplastic risk.
Str1 influences both tumor initiation and progression, independent of continued expression.
TIMP1 acts as a suppressor of Str1-mediated tumorigenesis.

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