title: Inflammation and IGF-I activate the Akt pathway in breast cancer.
abstract: Akt signaling may promote breast cancer progression and poor disease outcome. We hypothesized that serum insulin-like growth factor I (IGF-I) and a proinflammatory tumor environment induce phosphorylation of Akt and downstream targets of Akt in breast cancer. We studied the relationship between Akt pathway activation, IGF-I and markers of inflammation, e.g., nitric oxide synthase-2 (NOS2), cyclooxygenase-2 (COX2) and tumor phagocyte density, in 248 breast tumors. We also examined the association of Akt phosphorylation with breast cancer survival. We observed that phosphorylation of Akt, BAD and caspase-9 correlated strongly with the expression of the 2 proinflammatory enzymes, NOS2 and COX2, in breast tumors (p < 0.001; Spearman rank correlation). Both NOS2 and COX2 expression were independently associated with Akt phosphorylation in the multivariate analysis. Serum IGF-I concentrations and the IGF-I/IGFBP3 ratio correlated with Akt phosphorylation at Thr308 and Ser473 in breast tumors (p <or= 0.05; Spearman rank correlation). The association with Akt phosphorylation at Thr308 remained statistically significant in the multivariate analysis. Akt pathway activation was not associated with overall survival in the unstratified analysis, but we observed a statistical interaction between Akt phosphorylation and tumor phagocyte density on breast cancer survival (p(interaction) < 0.05). We further corroborated our findings in cell culture models by demonstrating that ANA-1 macrophages, nitric oxide and prostaglandin E(2) induce Akt phosphorylation in human breast cancer cells. In summary, a proinflammatory environment was found to activate the Akt pathway in breast cancer, and may modify the association between the Akt phosphorylation status and breast cancer survival.
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Prueitt
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Boersma
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Howe
authors.forename: Julie E
authors.initials: JE
authors.lastname: Goodman
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Thomas
authors.forename: Lei
authors.initials: L
authors.lastname: Ying
authors.forename: Candice M
authors.initials: CM
authors.lastname: Pfiester
authors.forename: Harris G
authors.initials: HG
authors.lastname: Yfantis
authors.forename: John R
authors.initials: JR
authors.lastname: Cottrell
authors.forename: Dong H
authors.initials: DH
authors.lastname: Lee
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Lorne J
authors.initials: LJ
authors.lastname: Hofseth
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.forename: Stefan
authors.initials: S
authors.lastname: Ambs
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010587:Phagocytosis; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015996:Survival Rate; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D051025:bcl-Associated Death Protein; D007334:Insulin-Like Growth Factor I; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D053453:Caspase 9