Immunohistochemical analysis of PDK1 expression in breast cancer

Diagnostic Pathology

Ruza Arsenic¹ 

[1] Institute of Pathology Charité, University Hospital Berlin, 10117 Berlin, Germany

关键词: Breast cancer;    PIK3CA;    PDK1;   

Others  :  801922
DOI  :  10.1186/1746-1596-9-82

 received in 2014-03-03, accepted in 2014-04-03,  发布年份 2014

【 摘 要 】

Background

3-phosphoinositide-dependent protein kinase-1 (PDK1) functions downstream of phosphoinositide 3-kinase (PIK3) and activates members of the AGC family of protein kinases that are known to play crucial roles in physiological processes associated with cell metabolism, growth, proliferation and survival. Changes in the expression and activity of PDK1 and several AGC kinases have been linked to human disease, including cancer.

Methods

We used immunohistochemical analysis to determine PDK1 expression in 241 tumors from patients with breast cancer in which we had previously analyzed PIK3CA mutation status.

Results

Moderate or high expression of PDK1 was observed in 213 of the 241 cases (88%). There was no correlation between PIK3CA mutation status and PDK1 overexpression.

Conclusion

Our findings indicate that PDK1 is independently activated in breast cancer and not only as part of the PIK3CA pathway, suggesting that PDK1 plays a specific and distinct role from the canonical PIK3/Akt pathway and promotes oncogenesis independently of AKT. Our data implicate PDK-1 and downstream components of the PDK-1 signaling pathway as promising therapeutic targets for the treatment of breast cancer.

【 授权许可】

   
2014 Arsenic; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Bayascas JR, Leslie NR, Parsons R, Fleming S, Alessi DR: Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN(+/-) mice. Curr Biol 2005, 15:1839-1846.
• [2]Fyffe C, Falasca M: 3-Phosphoinositide-dependent protein kinase-1 as an emerging target in the management of breast cancer. Cancer Manag Res 2013, 5:271-280.
• [3]Eser S, Reiff N, Messer M, Seidler B, Gottschalk K, Dobler M, Hieber M, Arbeiter A, Klein S, Kong B, Michalski CV, Schlitter AM, Esposito I, Kind AJ, Rad L, Schnieke AE, Baccarini M, Alessi DR, Rad R, Schmid RM, Schneider G, Saur D: Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell 2013, 23:406-420.
• [4]Fujiwara S, Kawano Y, Yuki H, Okuno J, Nosaka K, Mitsuya H, Hata H: PDK1 inhibition is a novel therapeutic target in multiple myeloma. Br J Cancer 2013, 108:170-178.
• [5]Pearn L, Fisher J, Burnett AK, Darley RL: The role of PKC and PDK1 in monocyte lineage specification by Ras. Blood 2007, 109:4461-4469.
• [6]Tan JLP, Li Z, Jiang X, Lim YC, Hooi SC, Yu Q: B55β-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer. Cancer Cell 2010, 18:459-471.
• [7]Zabkiewicz J, Pearn L, Hills RK, Morgan RG, Tonks A, Burnett AK, Darley RL: The PDK1 master kinase is overexpressed in acute myeloid leukemia and promotes PKC-mediated survival of leukemic blasts. Haematologica 2013, 98:xxx.
• [8]Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ, Hennessy BT, Tseng H, Pochanard P, Kim SY, Dunn IF, Schinzel AC, Sandy P, Hoersch S, Sheng Q, Gupta PB, Boehm JS, Reiling JH, Silver S, Lu Y, Stemke-Hale K, Dutta B, Joy C, Sahin AA, Gonzales-Angulo AM, Lluch A, Rameh LE, Jacks T, Root DE, Lander ES, Mills GB, Hahn WC, Sellers WR, Garraway LA: AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 2009, 16:21-32.
• [9]Oger M, Allaoui M, Elie N, Marnay J, Herlin P, Plancoulaine B, Chasle J, Becette V, Bor-Amgelier C: Impact of tumor heterogeneity on disease-free survival in a series of 368 patients treated for a breast cancer. Diagn Pathol 2013, 8:S43. BioMed Central Full Text
• [10]Cheng H, Qin Y, Fan H, Su P, Zhang X, Zhang H, Zhou G: Overexpression of CARM1 in breast cancer is correlated with poorly characterized clinicopathologic parameters and molecular subtypes. Diagn Pathol 2013, 8:129. BioMed Central Full Text
• [11]Maurer M, Su T, Saal LH, Koujak S, Hopkins BD, Barkley CR, Wu J, Nandula S, Dutta B, Xie Y, Chin YR, Kim DI, Ferris JS, Gruvberger-Saal SK, Laakso M, Wang X, Memeo L, Rojtman A, Matos T, Yu JS, Cordon-Cardo C, Isola J, Terry MB, Toker A, Mills GB, Zhao JJ, Murty W, Hibshoosh H, Parson R: 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res 2009, 69:6299-6306.
• [12]Arsenic R, Lehmann A, Budczies J, Koch I, Prinzler J, Kleine-Tebbe A, Schewe C, Loibl S, Dietel M, Denkert C: Analysis of PIK3CA mutations in breast cancer subtypes. Appl Immunohistochemistry Mol Morphol:AIMM/Offic Publ Soc Appl Immunohistochemistry 2014, 22:50-56.