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Role of PELP1/MNAR Signaling in Ovarian Tumorigenesis

¹ Department of Obstetrics and Gynecology and Cancer Research and Therapy Center at The University of Texas Health Science Center, San Antonio, Texas; ² University of Texas MD Anderson Cancer Center, Houston, Texas; ³ Tulane University, New Orleans, Louisiana; and ⁴ University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Ratna K. Vadlamudi, Division of Reproductive Research, Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 7836, San Antonio, TX 78229-3900. Phone: 210-567-4930; Fax: 210-567-4958; E-mail: vadlamudi{at}uthscsa.edu.

Key Words: nuclear receptor • coactivator • oncogene • ovarian cancer • nongenomic signaling

Emerging evidence suggests that nuclear receptor (NR) coregulators have potential to act as master genes and their deregulation can promote oncogenesis. Proline-, glutamic acid–, and leucine–rich protein-1 (PELP1/MNAR) is a novel NR coregulator. Its expression is deregulated in hormone-driven cancers. However, the role of PELP1/MNAR in ovarian cancer progression remains unknown. Analysis of serial analysis of gene expression data suggested deregulation of PELP1/MNAR expression in ovarian tumors. Western analysis of PELP1/MNAR in normal and serous ovarian tumor tissues showed 3- to 4-fold higher PELP1/MNAR expression in serous tumors compared with normal ovarian tissues. To examine the significance of PELP1/MNAR in ovarian cancer progression, we have generated model cells that overexpress PELP1/MNAR and ovarian cancer cells in which PELP1/MNAR expression is down-regulated by stable expression of PELP1/MNAR-specific shRNA. Down-regulation of PELP1/MNAR in cancerous ovarian model cells (OVCAR3) resulted in reduced proliferation, affected the magnitude of c-Src and protein kinase B (AKT) signaling, and reduced tumorigenic potential of ovarian cancer cells in a nude mouse model. PELP1/MNAR overexpression in nontumorigenic immortalized surface epithelial cells (IOSE cells) promoted constitutive activation of c-Src and AKT signaling pathways and promoted anchorage-independent growth. Immunohistochemical studies using human ovarian cancer tissue arrays (n = 123) showed that PELP1/MNAR is 2- to 3-fold overexpressed in 60% of ovarian tumors, and PELP1/MNAR deregulation occurs in all different types of ovarian cancer. Collectively, these results suggest that PELP1/MNAR signaling plays a role in ovarian cancer cell proliferation and survival, and that its expression is deregulated in ovarian carcinomas. [Cancer Res 2008;68(12):4902–9]

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