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Expression of the tumor suppressor gene ARHI in epithelial ovarian cancer is associated with increased expression of p21WAF1/CIP1 and prolonged progression-free survival.
Clin Cancer Res. 2004 Oct 01; 10(19):6559-66.CC

Abstract

PURPOSE

ARHI, an imprinted putative tumor suppressor gene, is expressed in normal ovarian epithelial cells, but its expression is down-regulated or lost in most ovarian cancer cell lines. Reexpression of ARHI in cancer cells induces p21(WAF1/CIP1), down-regulates cyclin D1 promoter activity and inhibits growth in cell culture and in heterografts. To determine the relevance of these observations to clinical cancer, we have now measured ARHI expression in normal, benign and malignant ovarian tissues using immunohistochemistry and in situ hybridization.

EXPERIMENTAL DESIGN

Paraffin embedded tissues from 7 normal ovaries, 22 cystadenomas and 42 borderline lesions were analyzed using standard immunoperoxidase and in situ hybridization techniques to assess ARHI expression. In addition, immunohistochemistry against ARHI was performed on a tissue microarray containing 441 consecutive cases of ovarian carcinoma.

RESULTS

Strong ARHI expression was found in normal ovarian surface epithelial cells, cysts and follicles using immunohistochemistry and in situ hybridization. Reduced ARHI expression was observed in tumors of low malignant potential as well as in invasive cancers. ARHI expression was down-regulated in 63% of invasive ovarian cancer specimens and could not be detected in 47%. When immunohistochemistry and in situ hybridization were compared, ARHI protein expression could be down-regulated in the presence of ARHI mRNA. ARHI expression was correlated with expression of p21(WAF1/CIP1) (P = 0.0074) but not with cyclin D1 and associated with prolonged disease free survival (P = 0.001). On multivariate analysis, ARHI expression, grade and stage were independent prognostic factors. ARHI expression did not correlate with overall survival.

CONCLUSIONS

Persistence of ARHI expression in epithelial ovarian cancers correlated with prolonged disease free survival and expression of the cyclin dependent kinase inhibitor p21(WAF1/CIP1).

Authors+Show Affiliations

Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15475444

Citation

Rosen, Daniel G., et al. "Expression of the Tumor Suppressor Gene ARHI in Epithelial Ovarian Cancer Is Associated With Increased Expression of p21WAF1/CIP1 and Prolonged Progression-free Survival." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 10, no. 19, 2004, pp. 6559-66.
Rosen DG, Wang L, Jain AN, et al. Expression of the tumor suppressor gene ARHI in epithelial ovarian cancer is associated with increased expression of p21WAF1/CIP1 and prolonged progression-free survival. Clin Cancer Res. 2004;10(19):6559-66.
Rosen, D. G., Wang, L., Jain, A. N., Lu, K. H., Luo, R. Z., Yu, Y., Liu, J., & Bast, R. C. (2004). Expression of the tumor suppressor gene ARHI in epithelial ovarian cancer is associated with increased expression of p21WAF1/CIP1 and prolonged progression-free survival. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 10(19), 6559-66.
Rosen DG, et al. Expression of the Tumor Suppressor Gene ARHI in Epithelial Ovarian Cancer Is Associated With Increased Expression of p21WAF1/CIP1 and Prolonged Progression-free Survival. Clin Cancer Res. 2004 Oct 1;10(19):6559-66. PubMed PMID: 15475444.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Expression of the tumor suppressor gene ARHI in epithelial ovarian cancer is associated with increased expression of p21WAF1/CIP1 and prolonged progression-free survival. AU - Rosen,Daniel G, AU - Wang,Lin, AU - Jain,Ajay N, AU - Lu,Karen H, AU - Luo,Robert Z, AU - Yu,Yinhua, AU - Liu,Jinsong, AU - Bast,Robert C,Jr PY - 2004/10/12/pubmed PY - 2005/3/30/medline PY - 2004/10/12/entrez SP - 6559 EP - 66 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 10 IS - 19 N2 - PURPOSE: ARHI, an imprinted putative tumor suppressor gene, is expressed in normal ovarian epithelial cells, but its expression is down-regulated or lost in most ovarian cancer cell lines. Reexpression of ARHI in cancer cells induces p21(WAF1/CIP1), down-regulates cyclin D1 promoter activity and inhibits growth in cell culture and in heterografts. To determine the relevance of these observations to clinical cancer, we have now measured ARHI expression in normal, benign and malignant ovarian tissues using immunohistochemistry and in situ hybridization. EXPERIMENTAL DESIGN: Paraffin embedded tissues from 7 normal ovaries, 22 cystadenomas and 42 borderline lesions were analyzed using standard immunoperoxidase and in situ hybridization techniques to assess ARHI expression. In addition, immunohistochemistry against ARHI was performed on a tissue microarray containing 441 consecutive cases of ovarian carcinoma. RESULTS: Strong ARHI expression was found in normal ovarian surface epithelial cells, cysts and follicles using immunohistochemistry and in situ hybridization. Reduced ARHI expression was observed in tumors of low malignant potential as well as in invasive cancers. ARHI expression was down-regulated in 63% of invasive ovarian cancer specimens and could not be detected in 47%. When immunohistochemistry and in situ hybridization were compared, ARHI protein expression could be down-regulated in the presence of ARHI mRNA. ARHI expression was correlated with expression of p21(WAF1/CIP1) (P = 0.0074) but not with cyclin D1 and associated with prolonged disease free survival (P = 0.001). On multivariate analysis, ARHI expression, grade and stage were independent prognostic factors. ARHI expression did not correlate with overall survival. CONCLUSIONS: Persistence of ARHI expression in epithelial ovarian cancers correlated with prolonged disease free survival and expression of the cyclin dependent kinase inhibitor p21(WAF1/CIP1). SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/15475444/Expression_of_the_tumor_suppressor_gene_ARHI_in_epithelial_ovarian_cancer_is_associated_with_increased_expression_of_p21WAF1/CIP1_and_prolonged_progression_free_survival_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15475444 DB - PRIME DP - Unbound Medicine ER -