Phospho-mTOR and phospho-4EBP1 in endometrial adenocarcinoma: association with stage and grade in vivo and link with response to rapamycin treatment in vitro.
OBJECTIVE
Endometrial adenocarcinoma, due to a frequent activation of PI3 K/AKT has been proposed as a candidate neoplasm for the treatment with mTOR inhibitors. Yet, data on the expression of mTOR cascade components in endometrial cancer are lacking.


METHODS
To provide a basis for futher studies with mTOR inhibitors, we used immunohistochemistry to evaluate the expression of activated mTOR pathway components in 57 endometrial cancer surgical specimens in vivo, and investigated in vitro the relation between the activation of AKT/mTOR and the response to rapamycin.


RESULTS
p-mTOR expression was associated with nuclear p-4EBP1 expression (P = 0.02), and was more frequent in tumors extending ouside the uterine corpus (P = 0.011). Nuclear p-4EBP1 expression was increased in carcinomas of poor differentiation (P = 0.012). In cultivated PTEN-deficient Ishikawa cells, in addition to an activation of AKT, a phosphorylation of mTOR and 4EBP1 was evident, while PTEN-wild type HEC-1A cells lacked AKT activation but revealed a reduced expression of p-mTOR and p-4EBP1. Rapamycin induced a growth reduction, which was clearly more pronounced in Ishikawa cells than in HEC-1A cells (P < 0.03) and could be observed for up to 6 days. CONCLUSISONS: Expression of mTOR and 4EBP1 characterize high-grade, high-stage endometrial adenocarcinomas and might be predictive markers of a response to rapamycin. Based on our results, we suggest that the expression of elements of the mTOR pathway in human tumor tissue should be further evaluated as a possible predictive marker in large-scale clinical studies as well as translational research protocols in clinical studies with mTOR inhibitors.
Darb-Esfahani
Silvia
S
Institute of Pathology, Charité Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany. silvia.darb-esfahani@charite.de
Faggad
Areeg
A
Noske
Aurelia
A
Weichert
Wilko
W
Buckendahl
Ann-Christin
AC
Müller
Berit
B
Budczies
Jan
J
Röske
Annika
A
Dietel
Manfred
M
Denkert
Carsten
C
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000230:Adenocarcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D018797:Cell Cycle Proteins; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D011494:Protein Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus