Abstract
There is a growing body of evidence indicating that calcitonin (CT) and calcitonin receptor (CTR) are involved in the regulation of cell growth, differentiation, and survival and in tissue development. However, the precise functional role of CT/CTR in breast cancer is still unknown. It is well established that the urokinase plasminogen activator (uPA) system plays an important role in breast cancer invasion and metastasis. The goal of this study was to investigate the effects of CT on regulation of the uPA system and invasive capacity of breast cancer cells. In the highly invasive MDA-MB-231 cell line, 10(-8) M CT decreased both uPA and uPAR mRNA and protein expression which was associated with inhibition of the extracellular signal-regulated kinase (ERK) 1/2 pathway. Furthermore, two weeks of CT administration to nude mice inhibited the expression of uPA mRNA in primary tumors by 25% (P<0.05), as compared to control, untreated animals. CT also inhibited the invasiveness of MDA-MB-231 cells by 37% (10(-8) M CT, P<0.05), as determined by a Matrigel invasion assay. To the best of our knowledge, this is the first report describing a direct effect of CT on breast cancer cell invasion. Our data might suggest a close link between CT signaling, the uPA-mediated pathway, and breast cancer invasion.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Northern
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Blotting, Western
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Calcitonin / pharmacology*
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Calcitonin / therapeutic use
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Cell Line, Tumor
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Cell Movement / drug effects*
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DNA, Neoplasm / biosynthesis
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Dose-Response Relationship, Drug
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Enzyme-Linked Immunosorbent Assay
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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MAP Kinase Signaling System / drug effects
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Mammary Neoplasms, Experimental / drug therapy*
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Neoplasm Invasiveness
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Phosphorylation / drug effects
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Plasminogen Activator Inhibitor 1 / genetics
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Plasminogen Activator Inhibitor 1 / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Receptors, Urokinase Plasminogen Activator
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Reverse Transcriptase Polymerase Chain Reaction
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Urokinase-Type Plasminogen Activator / genetics
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Urokinase-Type Plasminogen Activator / metabolism
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Xenograft Model Antitumor Assays
Substances
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DNA, Neoplasm
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PLAUR protein, human
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Plasminogen Activator Inhibitor 1
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Plaur protein, mouse
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RNA, Messenger
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Receptors, Cell Surface
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Receptors, Urokinase Plasminogen Activator
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Calcitonin
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Urokinase-Type Plasminogen Activator