title: Inhibition of breast cancer cell migration by activation of cAMP signaling.
abstract: Almost all deaths from breast cancer arise from metastasis of the transformed cells to other sites in the body. Hence, uncovering a means of inhibiting breast cancer cell migration would provide a significant advance in the treatment of this disease. Stimulation of the cAMP signaling pathway has been shown to inhibit migration and motility of a number of cell types. A very effective way of selectively stimulating cAMP signaling is through inhibition of cyclic nucleotide phosphodiesterases (PDEs). Therefore, we examined full expression profiles of all known PDE genes at the mRNA and protein levels in four human breast cancer cell lines and eight patients' breast cancer tissues. By these analyses, expression of almost all PDE genes was seen in both cell lines and tissues. In the cell lines, appreciable expression was seen for PDEs 1C, 2A, 3B, 4A, 4B, 4D, 5A, 6B, 6C, 7A, 7B, 8A, 9A, 10A, and 11A. In patients' tissues, appreciable expression was seen for PDEs 1A, 3B, 4A, 4B, 4C, 4D, 5A, 6B, 6C, 7A, 7B, 8A, 8B, and 9A. PDE8A mRNA in particular is prominently expressed in all cell lines and patients' tissue samples examined. We show here that stimulation of cAMP signaling with cAMP analogs, forskolin, and PDE inhibitors, including selective inhibitors of PDE3, PDE4, PDE7, and PDE8, inhibit aggressive triple negative MDA-MB-231 breast cancer cell migration. Under the same conditions, these agents had little effect on breast cancer cell proliferation. This study demonstrates that PDE inhibitors inhibit breast cancer cell migration, and thus may be valuable therapeutic targets for inhibition of breast cancer metastasis. Since PDE8A is expressed in all breast cancer samples, and since dipyridamole, which inhibits PDE8, and PF-04957325, a selective PDE8 inhibitor, both inhibit migration, it suggests that PDE8A may be a valuable novel target for treatment of this disease.
authors.affiliation: Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT, 06030-3505, United States.
authors.forename: Hongli
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT, 06030-3505, United States.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Claffey
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT, 06030-3105, United States.
authors.forename: Stefan
authors.initials: S
authors.lastname: Brocke
authors.affiliation: Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT, 06030-3505, United States. epstein@uchc.edu.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Epstein
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction
chemical_list: D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D000242:Cyclic AMP; D011494:Protein Kinases; C111878:cAMP phosphodiesterase kinase