27043

PELP1

proline, glutamate and leucine rich protein 1;PELP1;proline, glutamate and leucine rich protein 1

modulator of non-genomic activity of estrogen receptor|proline and glutamic acid rich nuclear protein|proline-, glutamic acid- and leucine-rich protein 1|transcription factor HMX3

17p13.2

protein-coding

Breast cancer metastasis is a major clinical problem. The molecular basis of breast cancer progression to metastasis remains poorly understood. PELP1 is an estrogen receptor (ER) coregulator that has been implicated as a proto-oncogene whose expression is deregulated in metastatic breast tumors and whose expression is retained in ER-negative tumors. We examined the mechanism and significance of PELP1-mediated signaling in ER-negative breast cancer progression using two ER-negative model cells (MDA-MB-231 and 4T1 cells) that stably express PELP1-shRNA. These model cells had reduced PELP1 expression (75% of endogenous levels) and exhibited less propensity to proliferate in growth assays in vitro. PELP1 downregulation substantially affected migration of ER-negative cells in Boyden chamber and invasion assays. Using mechanistic studies, we found that PELP1 modulated expression of several genes involved in the epithelial mesenchymal transition (EMT), including MMPs, SNAIL, TWIST, and ZEB. In addition, PELP1 knockdown reduced the in vivo metastatic potential of ER-negative breast cancer cells and significantly reduced lung metastatic nodules in a xenograft assay. These results implicate PELP1 as having a role in ER-negative breast cancer metastasis, reveal novel mechanism of coregulator regulation of metastasis via promoting cell motility/EMT by modulating expression of genes, and suggest PELP1 may be a potential therapeutic target for metastatic ER-negative breast cancer.

Proline-, glutamic acid- and leucine-rich protein-1/modulator of non-genomic activity of estrogen receptor (ER) (PELP1/MNAR) is a novel nuclear receptor (NR) co-activator that plays an essential role in the actions of ER. Emerging findings suggest that PELP1/MNAR is a novel proto-oncogene, whose expression is deregulated in several hormone-responsive cancers, including endometrial cancer. In this study, we demonstrate that PELP1/MNAR is widely expressed in endometrial carcinoma cell lines. To investigate its possible role in endometrial carcinoma progression, we adopted an RNA interference technology to downregulate PELP1/MNAR expression in Ishikawa endometrial carcinoma cells. PELP1/MNAR downregulation substantially reduced cell proliferation, and the cells in which PELP1/MNAR expression was knocked down also exhibited a decreased migration and invasion ability, as shown by Boyden chamber and invasion assays. The results showed that the expression of MMP-2 and MMP-9 was also decreased. These results suggest that PELP1/MNAR plays a role in endometrial cancer progression and metastasis, and that PELP1/MNAR may be a potential therapeutic target for endometrial cancer.

Estradiol (E2) and estrogen receptor (ER) signaling have been implicated in the development and progression of several cancers. Emerging evidence suggests that the status of ER coregulators in tumor cells plays an important role in hormonal responsiveness and tumor progression. Proline, glutamic acid, and leucine-rich protein-1 (PELP1/MNAR)-a novel ER coactivator that plays an essential role in the ER's actions and its expression-is deregulated in several hormonal responsive cancers. The precise function of PELP1/MNAR in cancer progression remains unclear, but PELP1 appears to function as a scaffolding protein, coupling ER with several proteins that are implicated in oncogenesis. Emerging evidence suggests that PELP1/MNAR increases E2-mediated cell proliferation and participates in E2-mediated tumorigenesis and metastasis.

PURPOSE: Ovarian cancer remains a major threat to women's health, partly due to difficulty in early diagnosis and development of metastases. A critical need exists to identify novel targets that curb the progression and metastasis of ovarian cancer. In this study, we examined whether the nuclear receptor coregulator PELP1 (proline-, glutamic acid-, leucine-rich protein-1) contributes to progression and metastatic potential of ovarian cancer cells and determined whether blocking of the PELP1 signaling axis had a therapeutic effect. EXPERIMENTAL DESIGN: Ovarian cancer cells stably expressing PELP1-shRNA (short hairpin RNA) were established. Fluorescent microscopy, Boyden chamber, invasion assays, wound healing, and zymography assays were performed to examine the role of PELP1 in metastasis. expression analysis of the model cells was conducted using tumor metastasis microarray to identify PELP1 Target genes. Therapeutic potential of PELP1-siRNA in vivo was determined using a nanoliposomal formulation of PELP1-siRNA-DOPC (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine) administered systemically in a xenograft model. RESULTS: PELP1 knockdown caused cytoskeletal defects and significantly affected the migratory potential of ovarian cancer cells. Microarray analysis revealed that PELP1 affected the expression of selective genes involved in metastasis including Myc, MTA1, MMP2, and MMP9. Zymography analysis confirmed that PELP1 knockdown caused a decrease in the activation of matrix metalloproteases (MMP) 2 and MMP9. Compared with control siRNA-DOPC-treated mice, animals injected with PELP1-siRNA-DOPC had 54% fewer metastatic tumor nodules, exhibited a 51% reduction in tumor growth and an 84% reduction in ascites volume. CONCLUSION: The results suggest that PELP1 signaling axis is a potential druggable target and liposomal PELP1-siRNA-DOPC could be used as a novel drug to prevent or treat ovarian metastasis.