Adenovirus-directed expression of Q227L-G alpha(s) inhibits growth of established tumors of later-stage human breast cancer cells in athymic mice.
Elevation of cAMP inhibits proliferation and expression of the transformed phenotype in several cell types. We studied the effects of elevation of cAMP and expression of mutant (Q227L) activated G alpha(s) on the proliferation and tumorigenic capability of the later stage, metastatic estrogen-independent human breast cancer cell lines MDA-231 and MDA-435. Our studies show that 8Br-cAMP inhibits proliferation of these cells in culture and their ability to form colonies in soft agar. This inhibition may occur by different mechanisms in the two cell types. In MDA-231 cells, cAMP elevation results in sustained expression of the cell cycle inhibitor p27kip1 and inhibition of CDK2 activity, whereas in MDA-435 cells inhibition of mitogen-activated protein (MAP) kinase 1,2 activity is observed. We tested whether these effects in culture could be translated into inhibition of tumor growth in vivo. Tumors were developed in athymic (Nu/Nu) mice by injections of MDA-231 or MDA-435 cells. Injection of Q227L-G alpha(s) expressing adenoviral vector into these established tumors inhibited further tumor growth under conditions where tumors injected with either saline or adenoviral vector containing beta-galactosidase grew up to four to five times their original size. These results raise the possibility that sustained elevation of cAMP may have therapeutic value in the treatment of estrogen-resistant later stage breast cancers.
Santore
Tara Ann
TA
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029.
Chen
Yibang
Y
Smit
Martine J
MJ
Iyengar
Ravi
R
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004815:Epidermal Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; D019205:GTP-Binding Protein alpha Subunits, Gs; D020962:Heterotrimeric GTP-Binding Proteins