Bcl-2 protein expression associated with resistance to apoptosis in clear cell adenocarcinomas of the vagina and cervix expressing wild-type p53.
BACKGROUND
Clear cell adenocarcinomas (CCAs) of the vagina and cervix are rare tumors that often overexpress wild-type p53. In vitro, expression of protooncogene bcl-2 can block p53-mediated apoptosis. The objective of this study was to determine if bcl-2 is expressed in CCAs and whether this expression is associated with inhibition of apoptosis.


METHODS
Twenty-one paraffin-embedded clear cell adenocarcinomas were immunohistochemically stained for bcl-2 (antibody M 887, Dako, Carpinteria, CA) and DNA fragmentation (ApopTag, Oncor, Gaithersburg, MD), a marker for apoptosis. Fifteen tumors were associated with in utero exposure to diethylstilbestrol (DES). Prior p53 gene analysis had indicated the presence of wild-type p53 in each tumor. Human lymphoid tissue containing bcl-2-expressing lymphocytes and DNase I-exposed CCA tissue sections were used as positive controls for the bcl-2 and apoptosis assays, respectively. Expression of bcl-2 and DNA fragmentation was classified (0 to 3+) according to percentage of positive cells and intensity of staining.


RESULTS
Expression of bcl-2 was identified in each CCA examined, and was strongly positive (2+ to 3+) in 18 of 21 samples. Despite the presence of wild-type p53, only 4 of 21 tumors showed evidence of apoptosis as assessed through DNA fragmentation.


CONCLUSIONS
DNA damage leads to increased intracellular p53 levels. Overexpression of p53 induces apoptosis as a means of protecting organisms from the development of malignancy. CCAs of the vagina and cervix, which contain wild-type p53 genes and often overexpress p53 protein, presumably have evolved mechanisms to avoid p53-induced apoptosis. Our observations are consistent with the hypothesis that overexpression of bcl-2 can inhibit p53-mediated apoptosis and suggest a mechanism by which these rare tumors can arise without mutation of the p53 gene.
Waggoner
S E
SE
Department of Obstetrics and Gynecology, University of Chicago, Illinois, USA.
Baunoch
D A
DA
Anderson
S A
SA
Leigh
F
F
Zagaja
V G
VG
D018262:Adenocarcinoma, Clear Cell / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis; D053938:DNA Fragmentation; D004054:Diethylstilbestrol / Q000009:adverse effects; D004968:Estrogens, Non-Steroidal / Q000009:adverse effects; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D002583:Uterine Cervical Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D014625:Vaginal Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology
D004968:Estrogens, Non-Steroidal; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D004054:Diethylstilbestrol