Inactivation of the candidate tumor suppressor par-4 in endometrial cancer.
Recently, it has been shown that mice deficient in the proapoptotic protein prostate apoptosis response 4 (Par-4) are specifically prone to develop endometrial carcinomas. Based on this, we have examined here the possible role of Par-4 as a tumor suppressor gene in human endometrial cancer. Using cDNA arrays, quantitative reverse transcription-PCR, and immunohistochemistry, we detected Par-4 down-regulation in approximately 40% of endometrial carcinomas. This alteration was not associated with phosphatase and tensin homologue (PTEN), K-RAS, or beta-catenin mutations, but was more frequent among tumors showing microsatellite instability (MSI) or among tumors that were estrogen receptor positive. Mutational analysis of the complete coding sequence of Par-4 in endometrial cancer cell lines (n = 6) and carcinomas (n = 69) detected a mutation in a single carcinoma, which was localized in exon 3 [Arg (CGA) 189 (TGA) Stop]. Interestingly, Par-4 promoter hypermethylation was detected in 32% of the tumors in association with low levels of Par-4 protein and was more common in MSI-positive carcinomas. Par-4 promoter hypermethylation and silencing was also detected in endometrial cancer cell lines SKUT1B and AN3CA, and reexpression was achieved by treatment with the demethylating agent 5'-aza-2'-deoxycytidine. Together, these data show that Par-4 is a relevant tumor suppressor gene in human endometrial carcinogenesis.
Moreno-Bueno
Gema
G
Breast and Gynecological Cancer Group, Tumor Suppression Group, Spanish National Cancer Center (CNIO), 3 Melchior Fernandez Almagro Street, Madrid E-28029, Spain.
Fernandez-Marcos
Pablo J
PJ
Collado
Manuel
M
Tendero
Mercedes J
MJ
Rodriguez-Pinilla
Socorro M
SM
Garcia-Cao
Isabel
I
Hardisson
David
D
Diaz-Meco
Maria T
MT
Moscat
Jorge
J
Serrano
Manuel
M
Palacios
Jose
J
D000328:Adult; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008969:Molecular Sequence Data; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; C101296:prostate apoptosis response-4 protein