Novel Role for PDEF in Epithelial Cell Migration and Invasion

Gunawardane, Ruwanthi N.; Sgroi, Dennis; Wrobel, Carolyn N.; Koh, Eugene Y.; Daley, George Q.; Brugge, Joan S.

doi:10.1158/0008-5472.can-05-1196

Cited by 78 publications

(93 citation statements)

References 31 publications

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“…Following the discovery of PDEF in year 2000 (35), much work has been done to understand the role of PDEF in the process of normal growth and development and in cancer progression. PDEF, a key Ets transcription factor has been studied by various groups involved in the process of tumor progression (17,36,37).…”

Section: Discussionmentioning

confidence: 99%

PDEF downregulates stathmin expression in prostate cancer

et al. 2012

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Abstract. The Ets proteins are a family of transcription factors characterized by an evolutionarily conserved DNA binding domain that controls key cellular processes. Prostate-derived Ets transcription factor (PDEF), a member of the Ets family, is reported to be present in tissues with high epithelial content, notably breast and prostate. However, the role of PDEF in cancer development is not fully understood. To gain insight into the molecular mechanisms associated with prostate cancer progression, we employed iTRAQ labeling followed by mass spectrometric (MS) analysis to identify candidate proteins that are differentially expressed in prostate cancer cells with or without PDEF. To this end, we overexpressed PDEF in PC3 human prostate cells using a tetracycline inducible system (Tet-On). Many differentially expressed proteins which play important roles in various cellular and biological processes were identified. Among them, stathmin (STMN), which is a microtubule (MT)-destabilizing protein, was found to be downregulated in multiple analyses. We demonstrated that re-expression of STMN reversed the antitumor properties of PDEF in PDEF-overexpressing PC3 cells. Using in vitro functional assays, we showed that STMN overexpression counteracted PDEF's effects against cell proliferation, colony formation and tumor migration. Similar results were further confirmed with the prostate cancer cell line CWR22rv1. In conclusion, many differentially expressed proteins were identified and STMN was found to be downregulated by PDEF.These results suggest that PDEF may inhibit prostate cancer progression by transcriptional downregulation of oncogenic STMN expression. Analyzing the association among differentially expressed proteins may provide a basis to better understand the molecular mechanisms underlying the process of cancer progression and development and further aid in designing therapeutics in the future. IntroductionProstate cancer is the most common cancer diagnosed among men and the second leading cause of death in American men, behind only lung cancer. The American Cancer Society (ACS) estimates about 1 man in 36 will die of prostate cancer (1). Although screening for prostate cancer, based on prostate specific antigen (PSA) has revolutionized early detection and diagnosis of the disease, the challenge that clinicians face are to determine which patients progress to aggressive disease (2,3). In order to determine the possibility of disease progression and ability to manage patient outcomes, it is necessary to better understand the molecular processes underlying the disease development and progression. Gene regulation is an important process in maintaining the integrity of cells for their proper growth and survival. Improper regulation of genes can lead to various diseases like cancer. The Ets family of transcription factors has been long investigated for their role in genetic loss of cellular homeostasis which results in development of various cancers. So far, 25 human and 26 murine Ets family members have been report...

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Section: Discussionmentioning

confidence: 99%

PDEF downregulates stathmin expression in prostate cancer

et al. 2012

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“…A recent report described synergistic cooperation between PDEF and Her2/neu or CSF-1R/CSF-1 in promoting anchorage independent growth, motility and invasiveness in normal and neoplastic breast and non-breast epithelial cell lines (15), suggesting that PDEF collaborates with initiating oncogenic signaling from these receptor tyrosine kinases to enhance tumor progression. In light of the latter understanding, our preliminary finding of an association of increased PDEF expression with Her2/neu over expression is very interesting and needs validation in a larger study.…”

Section: Discussionmentioning

confidence: 99%

“…Prostate derived Ets factor (PDEF) belongs to the Ets family of transcription factors that play an important role in normal as well as neoplastic development (11)(12)(13)(14)(15). However, despite such promise, our knowledge about the characteristics of PDEF expression in human cancer remains limited.…”

Section: Introductionmentioning

confidence: 99%

Expression characteristics of prostate-derived Ets factor support a role in breast and prostate cancer progression

et al. 2007

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The purpose of this study was to understand the characteristics of PDEF protein expression in breast and prostate cancer progression. A polyclonal antibody specific to PDEF was raised and reacted with tissue microarrays consisting of benign breast, in situ ductal, invasive ductal and invasive lobular breast carcinomas. The antibody was also reacted with tissue microarrays including benign prostate, prostate intra-epithelial neoplasias and prostate carcinomas. Increased expression of PDEF was identified in 18%, 50%, 46% and 51% of benign breast tissues, intraductal, invasive ductal and invasive lobular carcinomas, respectively. Importantly, in matched samples of benign breast versus tumor, 90% showed higher expression of PDEF in the tumor tissue. Moreover, in invasive breast carcinomas, increased PDEF expression tended to correlate with Her2/neu over expression. Increased expression of PDEF was also found in 27%, 33% and 40% of benign prostate tissues, PIN samples and prostate adenocarcinomas, respectively. Again, in matching samples of cancer versus benign and cancer versus PIN, 68% and 70% respectively showed increased expression in the malignant tissue. Moreover, PDEF was found to be more highly expressed in tumors with intermediate or high Gleason score compared to low grade tumors (P<0.01). Additionally, R1881 treatment induced PDEF expression in the LNCaP prostate tumor cell line, suggesting regulation of PDEF by androgens in vivo. Together, these results for the first time show frequent increased expression of PDEF protein in breast and prostate tumors and support a role for PDEF in breast and prostate cancer progression.

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“…20 Overexpression of Pdef has been found to stimulate cell mobility and invasion. 21 Based on these observations, it is generally thought that Ets proteins possess oncogenic properties. This theory was supported by the recent findings in prostate cancer that three Ets genes, Etv1, Erg and Etv4, were fused to an androgen inducible gene, TMPRSS2, by recurrent chromosomal translocation.…”

Section: Discussionmentioning

confidence: 99%

Profile of Ets gene expression in human breast carcinoma

Pan

Hu³

et al. 2007

Cancer Biology & Therapy

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Background: Ets genes encode a family of transcription factors that play key roles in cell proliferation, differentiation and apoptosis. Fusions of Ets genes with other targets have been described in Ewing's sarcoma, chronic myelomonocytic leukemia and more recently prostate carcinoma. Ets expression in breast carcinoma has not been comprehensively studied, and is the focus of this study.Methods: RT-Q-PCR was used to determine the expression of Ets genes in a panel of ten common breast cancer cell lines, two immortalized normal breast epithelial cell lines, and one primary culture of human mammary epithelial cells. Ets with altered expression in cancer cell lines were verified in primary breast tumors.Results: Transcripts of 21 of the 27 Ets genes were detected in either normal or cancer cells. Of the 21 detectable genes, 14 were expressed at a similar level in both normal and breast cancer cell lines. Four genes, Ehf, Elf3, Elf5 and Pdef, were expressed at higher levels in breast cancer cells than normal epithelials. Surprisingly, the expression of Elk3, Ets1 and Fli1 was repressed in breast cancer cells. The protein status of Ehf, Elf3, Pdef, Elk3, Ets1 and Fli1, strongly correlated with the transcript data, suggesting that Ets expression is regulated primarily at the transcriptional level. Similarly, Elf3, Pdef and Tel2 were overexpressed, while Elk3, Ets1 and Fli1 were under-expressed in primary breast tumor specimens in comparison with normal mammary tissues.Conclusions: Our study identified a subset of Ets genes with altered expression in breast carcinoma, implicating their roles in mammary tumorigenesis. While the Ets overexpression pattern is useful to uncover recurrent genetic alterations involving Ets genes, the repressed expression of several Ets genes suggests that some Ets proteins may play suppressor roles during breast cancer progression. Our results warrant detailed studies of individual Ets activity during mammary gland neoplasia.

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Novel Role for PDEF in Epithelial Cell Migration and Invasion

Cited by 78 publications

References 31 publications

PDEF downregulates stathmin expression in prostate cancer

PDEF downregulates stathmin expression in prostate cancer

Expression characteristics of prostate-derived Ets factor support a role in breast and prostate cancer progression

Profile of Ets gene expression in human breast carcinoma

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