Consequences of the loss of p53, RB1, and PTEN: relationship to gefitinib resistance in endometrial cancer.
OBJECTIVE
These studies demonstrate how loss of function mutations or downregulation of key tumor suppressors missing from type I and type II endometrial cancer cells contributes to carcinogenesis and to resistance to the EGFR inhibitor gefitinib (ZD1839).


METHODS
Cell models devoid of tumor suppressors PTEN and RB1 or PTEN were studied. PTEN, RB1 and p53 expression was reinstated, and the effects on cell cycle, apoptosis, and cell cycle regulators were evaluated.


RESULTS
In Ishikawa H cells that model type I endometrial cancer in the loss of PTEN and RB1, re-expressing PTEN and RB1 increased the apoptotic and G1 phases and decreased the S and G2-M phases, which further sensitize the cells to gefitinib. Expressing p53 in Hec50co that model type II tumors by loss of this tumor suppressor arrested cells at the G1-S checkpoint, and apoptosis was also induced. Yet this did not improve sensitivity to gefitinib. Modulation of the cell cycle regulators responsible for these changes is explored, and a potential new therapeutic target, MDM2, is identified.


CONCLUSIONS
The downregulation of p53 expression in type II Hec50co cells is linked to gefitinib resistance. In addition, the overexpression of MDM2, the principal factor that inhibits p53 function also occurs in these resistant cells. MDM2 phosphorylation is only partially blocked by gefitinib, and high MDM2 expression may relate to drug resistance.
Albitar
Lina
L
The Reproductive Molecular Biology Laboratory, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.
Carter
Mark B
MB
Davies
Suzy
S
Leslie
Kimberly K
KK
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D016147:Genes, Tumor Suppressor; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D011799:Quinazolines; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077156:Gefitinib