Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 2/2003

Open Access 01-04-2003 | Research article

Akt kinases in breast cancer and the results of adjuvant therapy

Authors: Olle Stål, Gizeh Pérez-Tenorio, Linda Åkerberg, Birgit Olsson, Bo Nordenskjöld, Lambert Skoog, Lars Erik Rutqvist

Published in: Breast Cancer Research | Issue 2/2003

Login to get access

Abstract

Background

The serine/threonine kinase Akt, or protein kinase B, has recently been a focus of interest because of its activity to inhibit apoptosis. It mediates cell survival by acting as a transducer of signals from growth factor receptors that activate phosphatidylinositol 3-kinase.

Methods

We analysed the expression of the isoforms Akt1 and Akt2 as well as phosphorylated Akt (pAkt) by immunohistochemistry in frozen tumour samples from 280 postmenopausal patients who participated in a randomised trial comparing cyclophosphamide–methotrexate–5-fluorouracil chemotherapy and postoperative radiotherapy. The patients were simultaneously randomised to tamoxifen or to no endocrine treatment.

Results

Marked staining was found in 24% of the tumours for Akt1, but in only 4% for Akt2. A low frequency of Akt2-positive cells (1–10%) was observed in another 26% of the tumours. pAkt was significantly associated with both Akt1 and Akt2 expression. Overexpression of erbB2 correlated significantly with pAkt (P = 0.0028). The benefit from tamoxifen was analysed in oestrogen receptor (ER)-positive patients. Patients with a negative status of Akt (no overexpression of Akt1, Akt2 or pAkt) showed significant benefit from tamoxifen. The relative rate of distant recurrence, with versus without tamoxifen, was 0.44 (95% confidence interval [CI], 0.25–0.79) for ER+/Akt1- patients, while it was 0.72 (95% CI, 0.34–1.53) for ER+/Akt1+ patients. The difference in rate ratio did not reach statistical significance. The rate of locoregional recurrence was significantly decreased with radiotherapy versus chemotherapy for Akt-negative patients (rate ratio, 0.23; 95% CI, 0.08–0.67; P = 0.0074), while no benefit was evident for the Akt-positive subgroup (rate ratio, 0.77; 95% CI, 0.31–1.9; P = 0.58). The interaction between Akt and the efficacy of radiotherapy was significant in multivariate analysis (P = 0.042).

Conclusion

Activation of the Akt pathway is correlated with erbB2 overexpression in breast cancer. The results suggest that Akt may predict the local control benefit from radiotherapy.
Literature
1.
Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet. 1998, 351: 1451-1467. 10.1016/S0140-6736(97)11423-4.CrossRef
2.
Zhang X, Yee D: Tyrosine kinase signalling in breast cancer: insulin-like growth factors and their receptors in breast cancer. Breast Cancer Res. 2000, 2: 170-175. 10.1186/bcr50.CrossRefPubMedPubMedCentral
3.
4.
Révillion F, Bonneterre J, Peyrat JP: ERBB2 oncogene in human breast cancer and its clinical significance. Eur J Cancer. 1997, 34: 791-808. 10.1016/S0959-8049(97)10157-5.CrossRef
5.
Kandel ES, Hay N: The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res. 1999, 253: 210-229. 10.1006/excr.1999.4690.CrossRefPubMed
6.
Page C, Lin HJ, Jin Y, Castle VP, Nunez G, Huang M, Lin J: Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis. Anticancer Res. 2000, 20: 407-416.PubMed
7.
Yuan ZQ, Sun M, Feldman RI, Wang G, Ma X, Jiang C, Coppola D, Nicosia SV, Cheng JQ: Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer. Oncogene. 2000, 19: 2324-2330. 10.1038/sj.onc.1203598.CrossRefPubMed
8.
Brognard J, Clark AS, Ni Y, Dennis PA: Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res. 2001, 61: 3986-3997.PubMed
9.
Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME: Regulation of neuronal survival by the serine–threonine protein kinase Akt. Science. 1997, 275: 661-665. 10.1126/science.275.5300.661.CrossRefPubMed
10.
Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J, Evan G: Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature. 1997, 385: 544-548. 10.1038/385544a0.CrossRefPubMed
11.
Kulik G, Klippel A, Weber MJ: Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Mol Cell Biol. 1997, 17: 1595-1606.CrossRefPubMedPubMedCentral
12.
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997, 91: 231-241.CrossRefPubMed
13.
del Peso L, Gonzalez-Carcia M, Page C, Herrera R, Nunez G: Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science. 1997, 278: 687-689. 10.1126/science.278.5338.687.CrossRefPubMed
14.
Kennedy SG, Kandel ES, Cross TK, Hay N: Akt/protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol. 1999, 19: 5800-5810.CrossRefPubMedPubMedCentral
15.
Cantley LC, Neel BG: New insights into tumour suppression: PTEN suppresses tumour formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA. 1999, 96: 4240-4245. 10.1073/pnas.96.8.4240.CrossRefPubMedPubMedCentral
16.
Lu Y, Lin YZ, LaPushin R, Cuevas B, Fang X, Yu SX, Davies MA, Khan H, Furui T, Mao M, Zinner R, Hung MC, Steck P, Siminovitch K, Mills GB: The PTEN/MMAC1/TEP tumour suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene. 1999, 18: 7034-7045. 10.1038/sj.onc.1203183.CrossRefPubMed
17.
Weng LP, Smith WM, Dahia PL, Ziebold U, Gil E, Lees JA, Eng C: PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1 arrest followed by cell death. Cancer Res. 1999, 59: 5808-5814.PubMed
18.
Stambolic V, Tsao MS, Macpherson D, Suzuki A, Chapman WB, Mak TW: High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice. Cancer Res. 2000, 60: 3605-3611.PubMed
19.
Jones PF, Jakubowicz T, Hemmings BA: Molecular cloning of a second form of rac protein kinase. Cell Regulat. 1991, 2: 1001-1009.
20.
Altomare DA, Guo K, Cheng JQ, Sonoda G, Walsh K, Testa JR: Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene. Oncogene. 1995, 11: 1055-1060.PubMed
21.
Nakatani K, Sakaue H, Thompson DA, Weigel RJ, Roth RA: Identification of a human Akt3 (protein kinase B γ) which contains the regulatory serine phosphorylation site. Biochem Biophys Res Commun. 1999, 257: 906-910. 10.1006/bbrc.1999.0559.CrossRefPubMed
22.
Altomare DA, Lyons GE, Mitsuuchi Y, Cheng JQ, Testa JR: Akt2 mRNA is highly expressed in embryonic brown fat and the AKT2 kinase is activated by insulin. Oncogene. 1998, 16: 2407-2411. 10.1038/sj.onc.1201750.CrossRefPubMed
23.
Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton TC, Tsichlis PN, Testa JR: AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc Natl Acad Sci USA. 1992, 89: 9267-9271.CrossRefPubMedPubMedCentral
24.
Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, Wan M, Dubeau L, Scambia G, Masciullo V, Ferrandina G, Benedetti Panici P, Mancuso S, Neri G, Testa JR: Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer. 1995, 64: 280-285.CrossRefPubMed
25.
Ruggeri BA, Huang L, Wood M, Cheng JQ, Testa JR: Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol Carcinogen. 1998, 21: 81-86. 10.1002/(SICI)1098-2744(199802)21:2<81::AID-MC1>3.0.CO;2-R.CrossRef
26.
Rutqvist LE, Cedermark B, Glas U, Johansson H, Rotstein S, Skoog L, Somell A, Theve T, Askergren J, Friberg S, Bergström J, Blomstedt B, Räf L, Slifversvärd C, Einhorn J: Radiotherapy, chemotherapy, and tamoxifen as adjuncts to surgery in early breast cancer: a summary of three randomised trials. Int J Radiat Oncol Biol Phys. 1989, 16: 629-639.CrossRefPubMed
27.
Stål O, Sullivan S, Sun X-F, Wingren S, Nordenskjold B: Simultaneous analysis of c-erbB-2 expression and DNA content in breast cancer using flow cytometry. Cytometry. 1994, 16: 160-168.CrossRefPubMed
28.
Stål O, Klintenberg C, Sullivan S, and the Southeast Sweden Breast Cancer Group: Overexpression of c-erbB-2 protein and locoregional recurrence in node-positive breast cancer. Breast. 1997, 6: 354-360.CrossRef
29.
Stål O, Borg Å, Fernö M, Källström A-C, Malmström P, Nordenskjöld B, and members of the South Sweden Breast Cancer Group and the Southeast Sweden Breast Cancer Group: erbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer. Ann Oncol. 2000, 11: 1545-1550. 10.1023/A:1008313310474.CrossRefPubMed
30.
Cox DR: Regression models and life tables. J R Stat Soc B. 1972, 34: 187-220.
31.
Kaplan M, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958, 53: 457-481.CrossRef
32.
Attwell S, Roskelley C, Dedhar S: The integrin-linked kinase (ILK) suppresses anoikis. Oncogene. 2000, 19: 3811-3815. 10.1038/sj.onc.1203711.CrossRefPubMed
33.
Rytomaa M, Lehmann K, Downward J: Matrix detachment induces caspase-dependent cytochrome c release from mitochondria: inhibition by PKB/Akt but not Raf signalling. Oncogene. 2000, 19: 4461-4468. 10.1038/sj.onc.1203805.CrossRefPubMed
34.
Ahmad S, Singh N, Glazer RI: Role of AKT1 in 17β-estradiol-and insulin-like growth factor I (IGF-I)-dependent proliferation and prevention of apoptosis in MCF-7 breast carcinoma cells. Biochem Pharmacol. 1999, 58: 425-430. 10.1016/S0006-2952(99)00125-2.CrossRefPubMed
35.
Bacus SS, Altomare DA, Lyass L, Chin DM, Farrell MP, Gurova K, Gudkov A, Testa JR: AKT2 is frequently upregulated in HER-2/neu-positive breast cancers and may contribute to tumor aggressiveness by enhancing cell survival. Oncogene. 2002, 21: 3532-3540. 10.1038/sj.onc.1205438.CrossRefPubMed
36.
Pérez-Tenorio G, Stål O, and members of the Southeast Sweden Breast Cancer Group: Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer. 2002, 86: 540-545. 10.1038/sj.bjc.6600126.CrossRefPubMedPubMedCentral
37.
Sun M, Paciga JE, Feldman RI, Yuan Z, Coppola D, Lu YY, Shelley SA, Nicosio SV, Cheng JQ: Phosphatidylinositol-3-OH kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor α (Erα) via interaction between ERα and PI3K. Cancer Res. 2001, 61: 5985-5991.PubMed
38.
Nakatani K, Thompson DA, Barthel A, Sakaue H, Liu W, Weigel RJ, Roth RA: Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. J Biol Chem. 1999, 274: 21528-21532. 10.1074/jbc.274.31.21528.CrossRefPubMed
39.
Lobenhofer EK, Huper G, Iglehart JD, Marks JR: Inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase activity in MCF-7 cells prevents oestrogen-induced mitogenesis. Cell Growth Differ. 2000, 11: 99-110.PubMed
40.
Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H: Phosphatidylinositol 3-kinase/AKT-mediated activation of oestrogen receptor alpha: a new model for anti-oestrogen resistance. J Biol Chem. 2001, 276: 9817-9824. 10.1074/jbc.M010840200.CrossRefPubMed
41.
Chen RH, Su YH, Chuang RL, Chang TY: Suppression of transforming growth factor-beta-induced apoptosis through a phosphatidylinositol 3-kinase/Akt-dependent pathway. Oncogene. 1998, 17: 1959-1968. 10.1038/sj.onc.1202111.CrossRefPubMed
42.
Mende I, Malstrom S, Tsichlis PN, Vogt PK, Aoki M: Oncogenic transformation induced by membrane-targeted Akt2 and Akt3. Oncogene. 2001, 20: 4419-4423. 10.1038/sj.onc.1204486.CrossRefPubMed
43.
Berry DA, Muss HB, Thor AD, Dressler L, Liu ET, Broadwater G, Budman DR, Henderson IC, Barcos M, Hayes D, Norton L: HER-2/neu and p53 expression versus tamoxifen resistance in oestrogen receptor-positive, node-positive breast cancer. J Clin Oncol. 2000, 18: 3471-3479.PubMed
44.
Bowers DC, Fan S, Walter KA, Abounader R, Williams JA, Rosen EM, Laterra J: Scatter factor/hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase- and AKT-dependent pathways. Cancer Res. 2000, 60: 4277-4283.PubMed
45.
Fan S, Ma YX, Wang JA, Yuan RQ, Meng Q, Cao Y, Laterra JJ, Goldberg ID, Rosen EM: The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signalling through phosphatidyl inositol 3' kinase. Oncogene. 2000, 19: 2212-2223. 10.1038/sj.onc.1203566.CrossRefPubMed
46.
Altiok S, Batt D, Altiok N, Papautsky A, Downward J, Roberts TM, Avraham H: Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-kinase/AKT in breast cancer cells. J Biol Chem. 1999, 274: 32274-32278. 10.1074/jbc.274.45.32274.CrossRefPubMed
Metadata
Title
Akt kinases in breast cancer and the results of adjuvant therapy
Authors
Olle Stål
Gizeh Pérez-Tenorio
Linda Åkerberg
Birgit Olsson
Bo Nordenskjöld
Lambert Skoog
Lars Erik Rutqvist
Publication date
01-04-2003
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 2/2003
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr569

Other articles of this Issue 2/2003

Breast Cancer Research 2/2003 Go to the issue

Commentary

β-Catenin: a transforming actor on many stages

Research article

Id-1 is not expressed in the luminal epithelial cells of mammary glands

Review

Host microenvironment in breast cancer development: Epithelial–mesenchymal transition in breast cancer development

Commentary

Trastuzumab, an appropriate first-line single-agent therapy for HER2-overexpressing metastatic breast cancer

Research article

A candidate metastasis-associated DNA marker for ductal mammary carcinoma

Article selection

Articles selected from Faculty of 1000 in May 2003
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits