Up-regulation of Akt3 in Estrogen Receptor-deficient Breast Cancers and Androgen-independent Prostate Cancer Lines

Abstract

We measured the insulin-stimulated amount of Akt1, Akt2, and Akt3 enzymatic activities in four breast cancer cell lines and three prostate cancer cell lines. In the estrogen receptor-deficient breast cancer cells and the androgen-insensitive prostate cells, the amount of Akt3 enzymatic activity was approximately 20 -60-fold higher than in the cells that were estrogen-or androgen-responsive. In contrast, the levels of Akt1 and -2 were not increased in these cells. The increase in Akt3 enzyme activity correlated with an increase in both Akt3 mRNA and protein. In a prostate cancer cell line lacking the tumor suppressor PTEN (a lipid and protein phosphatase), the basal enzymatic activity of Akt3 was constitutively elevated and represented the major active Akt in these cells. Finally, reverse transcription-PCR was used to examine the Akt3 expression in 27 primary breast carcinomas. The expression levels of Akt3 were significantly higher in the estrogen receptor-negative tumors in comparison to the estrogen receptor-positive tumors. To see if the increase in Akt3 could be due to chromosomal abnormalities, the Akt3 gene was assigned to human chromosome 1q44 by fluorescence in situ hybridization and radiation hybrid cell panel analyses. These results indicate that Akt3 may contribute to the more aggressive clinical phenotype of the estrogen receptornegative breast cancers and androgen-insensitive prostate carcinomas.

Akt2 is required for macrophage chemotaxis

“…1A). In the control experiments, all three Akt isoforms were detected in MDA-MB-231 cells, human breast cancer cells, consistent with previous reports [14]. When THP-1 cells were co-cultured with MCF-7, a representative breast cancer cell line, Western blotting analysis revealed an increase in Akt phosphorylation at both 308 and 473 residues, suggesting that breast cancer cells can stimulate Akt activation in macrophage (Fig.…”

“…while Akt3 shows a more restricted expression pattern [14]. Both genetic and molecular studies revealed that Akt isozymes are regulated by PI3 Kinases/PDK1 or mTOR [15].…”

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

“…Akt gene amplification has been observed in prostate cancer 78,79 and other malignancies including ovarian cancer, 80,81 pancreatic cancer, 82 gastric cancer, 83 thyroid cancer, 84 and breast cancer. 80,85 Elevated Akt expression and kinase activities are associated with a hormone-resistant phenotype and correlates with a poor prognosis in human prostate cancer and breast cancer.…”

“…80,85 Elevated Akt expression and kinase activities are associated with a hormone-resistant phenotype and correlates with a poor prognosis in human prostate cancer and breast cancer. 78,79,85,86 Upstream of Akt, amplification of PI3-K has been reported for prostate, 79 ovarian, 87,88 colon, 88 and breast cancer. 85 Several protein-tyrosine kinases (PTKs), which act upstream of the PI3-K and are important regulators of the PI3-K-Akt pathway, have been found overexpressed in various cancers because of activating mutations or other genetic alterations.…”

Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines

“…The AKT 3 primers were: forward primer 5 0 -ATGAGCGATGT TACCATTGT-3 0 (corresponding to position 1 -20, GenBank accession number NM_005465) and reverse primer 5 0 -CAGTCTGTCTGCTACAGCCTGGATA-3 0 (corresponding to positions 327 -303) (Nakatani et al, 1999). PCR program for all AKT isoforms was 30 cycles of 941C for 45 s, 551C for 45 s and 721C for 45 s.…”