Provasopressin expression by breast cancer cells: implications for growth and novel treatment strategies.
The arginine vasopressin (AVP) gene is expressed in certain cancers such as breast cancer, where it is believed to act as an autocrine growth factor. However, little is known about the regulation of the AVP protein precursor (proAVP) or AVP-mediated signaling in breast cancer and this study was undertaken to address some of the basic issues. The cultured cell lines examined (Mcf7, Skbr3, BT474, ZR75, Mcf10a) and human breast cancer tissue extract were found to express proAVP mRNA. Western analysis revealed multiple forms of proAVP protein were present in cell lysates, corresponding to those detected in human hypothalamus extracts. Monoclonal antibodies directed against different regions of proAVP bound to intact live Mcf7 and Skbr3 cells. Dexamethasone increased the amount of proAVP-associated glycopeptide (VAG) secreted by Skbr3 cells and a combination of dexamethasone, IBMX and 8br-cAMP increased cellular levels of VAG. Exogenous AVP (1, 10, and 100 nM) elevated phospho-ERK1/2 levels, and increased cell proliferation was observed in the presence of 10 nM AVP. Concurrent treatment with the V1a receptor antagonist SR49059 reduced the effects of AVP on proliferation in Mcf7 cells, and abolished it in Skbr3 cells. Results here show that proAVP components are found at the surface of Skbr3 and Mcf7 cells and are also secreted from these cells. In addition, they show that AVP promotes cancer cell growth, apparently through a V1-type receptor-mediated pathway and subsequent ERK1/2 activation. Thus, strategies for targeting proAVP should be examined for their effectiveness in diagnosing and treating breast cancer.
Keegan
Brendan P
BP
Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756, USA.
Akerman
Bonnie L
BL
Péqueux
Christel
C
North
William G
WG
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology; D001127:Arginine Vasopressin / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D006020:Glycopeptides / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D007124:Immunoenzyme Techniques; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D006020:Glycopeptides; D010726:Phosphodiesterase Inhibitors; D011498:Protein Precursors; D001127:Arginine Vasopressin; C016276:8-bromocyclic GMP; D003907:Dexamethasone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine