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Cell density-dependent regulation of matrix metalloproteinase and TIMP expression in differently tumorigenic breast cancer cell lines.

Abstract：

:Matrix metalloproteinases (MMPs) play a key role in cellular invasion and growth. Recent observations on tumor tissue samples suggest that MMP activity is altered in relation to cell density. Therefore, we examined MMP(-1,-2,-3,-8,-9,-10,-11 and -13) and TIMP-1/-2 expression of well-defined cell densities in breast carcinoma cell lines with differing in vivo tumorigenicity/invasiveness (MCF-7 < MDA-MB-468 < MDA-MB-231 < MDA-MB-435). Chemoinvasion assays were performed to link the in vitro data to the in vivo behavior. In accord with previous in vivo data, expression levels of most MMPs decreased significantly with increasing cell density and correlated well with a lower in vitro invasiveness of confluent cells. Since these data suggested that cell density regulates transcription and the promoter regions of most MMPs have AP-1 transcription factor binding consensus sequences, we tested whether functional AP-1 protein was involved in the mechanism of MMP downregulation by cell density. A role for AP-1 was confirmed by over-expression of c-Jun and c-fos in confluent MDA-MB-231 cells, showing with c-Jun increased MMP-2 (5-fold), MMP-3 (1.6-fold), and MMP-9 (160-fold) expression, as well as enhanced invasive potential, while TIMP-1 expression was down-regulated (2-fold) when compared to vector controls. Our data provide clear evidence that cell density regulates major MMPs and TIMPs which are controlled by AP-1 activity so that ultimately a major regulation pathway for the control of the invasive potential of tumor cells is presented.

journal_name

Exp Cell Res

journal_title

Experimental cell research

authors

Bachmeier BE,Albini A,Vené R,Benelli R,Noonan D,Weigert C,Weiler C,Lichtinghagen R,Jochum M,Nerlich AG

doi

10.1016/j.yexcr.2004.12.019

keywords:

subject

Has Abstract

pub_date

2005-04-15 00:00:00

pages

83-98

issue

1

eissn

0014-4827

issn

1090-2422

pii

S0014-4827(04)00749-9

journal_volume

305

pub_type

杂志文章

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