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. 2007 Mar 1;67(5):1927-34.
doi: 10.1158/0008-5472.CAN-06-2687.

Inactivation of the candidate tumor suppressor par-4 in endometrial cancer

Gema Moreno-Bueno  1 , Pablo J Fernandez-Marcos, Manuel Collado, Mercedes J Tendero, Socorro M Rodriguez-Pinilla, Isabel Garcia-Cao, David Hardisson, Maria T Diaz-Meco, Jorge Moscat, Manuel Serrano, Jose Palacios
Affiliations

Inactivation of the candidate tumor suppressor par-4 in endometrial cancer

Gema Moreno-Bueno et al. Cancer Res. .

Abstract

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.

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