CELL BIOLOGY AND METABOLISM
Up-regulation of Akt3 in Estrogen Receptor-deficient Breast Cancers and Androgen-independent Prostate Cancer Lines*

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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 receptor-negative breast cancers and androgen-insensitive prostate carcinomas.

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This work was supported in part by an American Diabetes Association mentor-based postdoctoral fellowship (to K. N.), a grant from the Pfeiffer foundation, National Institutes of Health (NIH) Grants DK 34926 (to R. A. R.) and CA63251 and CA77350 (to R. J. W.), a Feodor-Lynen Fellowship of the Alexander von Humboldt-Stiftung (to A. B.), NIH National Research Service Award Grant F32-CA69751 (to D. A. T.), and an American College of Surgeons Clowes Career Development Award (to R. J. W.). The Breast Cancer Resource of the Department of Pathology, New York University Medical Center, is funded by Department of the Army Grant DAMD 17-94-J-4177.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.