Invasiveness of breast cancer cells MDA-MB-231 through extracellular matrix is increased by the estradiol metabolite 4-hydroxyestradiol.

Abstract

In malignant breast cancer, estrogen metabolism is altered, favoring the accumulation of hydroxyestradiols, which can generate free radicals. These reactive species can activate matrix metalloproteinases (MMPs), which in turn can hydrolyze the proteins of the extracellular matrix (ECM) that act as a barrier to tumor cell passage. The aim of this study was to determine whether reactive oxygen species generated by 4-hydroxyestradiol (4-OHE(2)) can activate MMP-2 and then enhance the invasiveness of breast cancer cells MDA-MB-231 in vitro. Enzymatic assay and gel zymography demonstrated that 4-OHE(2) at a concentration as low as 10(-8) M led to the conversion of proMMP-2 to active MMP-2. Activation of proMMP-2 by 4-OHE(2) was inhibited by the Cu,Zn-SOD supporting the involvement of the free radical superoxide anion (O(2)(*-)). Using invasion chambers coated with matrigel (artificial ECM), 4-OHE(2) (10(-8) M) enhanced the invasiveness of MDA-MB-231 breast cancer cells by 3-fold. The addition of Cu,Zn-SOD reduced the invasiveness of MDA-MB-231 cells by more than 2-fold, supporting the involvement of O(2)(*-) generated by 4-OHE(2). Addition of an MMP-2 inhibitor completely inhibited the enhancement of invasiveness induced by 4-OHE(2), which demonstrates the importance of activating MMP-2 by 4-OHE(2). On the other hand, estradiol, which does not have a catechol structure, did not generate free radicals, and it could not activate proMMP-2 or enhance the invasiveness of beast cancer cells. Although these data need to be confirmed in an animal model, this study suggests that the accumulation of 4-OHE(2) in breast tumors could enhance the invasiveness of breast cancer cells.

• Authors: Benoit Paquette, Martine Bisson, Catherine Baptiste, Hélène Therriault, Rosalie Lemay, André M Cantin
• Journal: International journal of cancer (Int J Cancer) Vol. 113 Issue 5 Pg. 706-11 (Feb 20 2005) ISSN: 0020-7136 [Print] United States
• PMID: 15499624 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2004 Wiley-Liss, Inc.

Chemical References

• Culture Media, Conditioned
• Drug Combinations
• Estrogens, Catechol
• Laminin
• Peptide Fragments
• Proteoglycans
• Reactive Oxygen Species
• Superoxides
• matrigel
• Estradiol
• Collagen
• 4-hydroxyestradiol
• Superoxide Dismutase
• Matrix Metalloproteinase 2
• Oxygen

Topics

• Breast Neoplasms (enzymology, pathology)
• Collagen (chemistry)
• Culture Media, Conditioned
• Drug Combinations
• Enzyme Activation (drug effects)
• Estradiol (analogs & derivatives, pharmacology)
• Estrogens, Catechol (pharmacology)
• Extracellular Matrix (metabolism)
• Female
• Humans
• Laminin (chemistry)
• Matrix Metalloproteinase 2 (metabolism)
• Neoplasm Invasiveness
• Oxygen (metabolism)
• Peptide Fragments (metabolism)
• Proteoglycans (chemistry)
• Reactive Oxygen Species (metabolism)
• Superoxide Dismutase (metabolism)
• Superoxides (metabolism)