Letrozole as a potent inhibitor of cell proliferation and expression of metalloproteinases (MMP-2 and MMP-9) by human epithelial breast cancer cells.
P450 aromatase catalyzes the conversion of androgens to estrogens and plays a key role in the cell growth of hormone-dependent breast cancer in postmenopausal women. On the other hand, matrix metalloproteinases (MMPs), which can degrade almost all components of the extracellular matrix, play a crucial role in tumor cell invasion and cancer metastasis. In the present study the effect of letrozole on cell proliferation of estrogen receptor (ER)-positive MCF-7 human epithelial breast cancer and MCF-12A human mammary epithelial cells was studied. The effect of letrozole on the in vitro release of MMPs, particularly type IV collagenases (MMP-2 and MMP-9), by the ER-positive MCF-7 cells was also investigated, using a solid-phase method of high sensitivity and accuracy. Using RNA isolates from cell lines MCF-7 and MCF-12A, reverse transcriptase-polymerase chain reaction analysis revealed that only MCF-7 cells express the P450 aromatase gene. Study of the effects of letrozole alone and the hormones 17-beta-estradiol, testosterone and 4-androstene-3, 17-dione in the presence and absence of letrozole on cell growth at the DNA synthesis level showed that letrozole significantly suppressed the endogenous aromatase-induced proliferation of MCF-7 cells. The majority of MMPs secreted by MCF-7 cells were identified in their pro-forms, which was in accordance with the low metastatic potential determined for these cells. After treatment of cells with letrozole (10 nM) for 24 and 48 h, significant inhibition of MMP levels was obtained. Furthermore, concurrent treatment of MCF-7 cells with 17-beta-estradiol in the presence of letrozole significantly suppressed the estradiol-induced stimulation of MMP levels. The data obtained suggest that letrozole is a potent in vitro inhibitor of cell proliferation and of type IV collagenases expressed by ER-positive MCF-7 cells and may be of value for suppressing breast tumor growth and invasiveness.
Mitropoulou
Theoni N
TN
Department of Chemistry, Section of Organic Chemistry, Biochemistry and Natural Products, Laboratory of Biochemistry, University of Patras, Patras, Greece.
Tzanakakis
George N
GN
Kletsas
Dimitris
D
Kalofonos
Haralabos P
HP
Karamanos
Nikas K
NK
D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D000077289:Letrozole; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006728:Hormones; D009570:Nitriles; D012333:RNA, Messenger; D014230:Triazoles; D000077289:Letrozole; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9