Cell Signalling Factors in Breast Tumors. Tumor Cell Distribution May Define Tumors with Different Oncogenic Pathways Activated. The Critical Role of the Pathologist in Its Evaluation
V Peg, B Pons, MA Vazquez, EA Martinez, T Moline, O Cordoba, JL Lirola, S Ramon y Cajal. H.U.Vall Hebron, Barcelona, Spain; H.U. Vall Hebron, Barcelona, Spain
Background: Cell signalling is a crucial cellular pathway in breast carcinomas with a myriad of oncogenic alterations involved. The cell signals converge through a few pathways like pAKT,pMAPK and mTOR.Downstream mTOR factors such as pS6,p4E-BP1 and eIF4E/eIF4G control final cap-dependent protein traslation.Because breast tumors show a clear heterogeneity,we studied whether a diffuse or patchy immunohistochemical expression of downstream mTOR factors throughout the tumors could reflect a constitutive activation of the pathway or indicate complex concomitant epigenetic and oncogenic signals.
Design: We studied 34 primary tumors and 32 lymph node metastasis.By immunohistochemistry, real time-PCR and WB we evaluated the expression of 4E-BP1,p4E-BP1,peIF4E and eIF4G.Immunohistochemistry alone was performed for pMAPK and pS6.The expression of these factors was evaluated in whole sections of tumors according to a semi-quantitative score and to their tumoral distribution.The results were correlated with levels of protein and mRNA,tumor grade and metastasis.
Results: In our series,4E-BP1,p4E-BP1,eIF4E and peIF4G showed a predominant diffuse pattern of expression while pMAPK displayed a peripheral or patchy distribution in 57% cases and pS6 showed a patchy distribution in more than 70%.Interestingly,pS6 was stronger in the invasive border.Tumors with a diffuse expression of pS6 were usually grade III (65%) and had lymph node involvement (75%).The pattern of expression was the same in the primary tumor and in its metastasis.4E-BP1 and eIF4E study by WB and RT-PCR did not show a linear correlation between protein levels,mRNA or immunohistochemistry results.
Conclusions: 4E-BP1 and eIF4E protein expression levels associate with high grade tumors and lymph node involvement.Moreover,they show a diffuse and then constitutive expression while pMAPK and pS6 show a great heterogeneity with a predominant peripherical distribution.These results support that 4E-BP1 can reflect oncogenic activation of other cellular pathways in addition to mTOR Interestingly,a pS6 diffuse pattern (constitutive mTOR activation) associates with histological grade and metastasis.Finally, these results underline the critical role of the pathologist in the evaluation of cell signaling factors and the pitfalls that can be made from frozen tissues studies because of the tumor heterogeneity of many of these markers.
Monday, March 9, 2009 1:00 PM
Poster Session II # 55, Monday Afternoon