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(The) role of interferon, gamma-inducible protein 16 in the estrogen signaling during breast cancer progression : 유방암 진행과정의 에스트로겐 신호전달에서 Interferon, gamma-inducible protein 16의 역할 규명
DC Field | Value | Language |
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dc.contributor.advisor | 이미옥 | - |
dc.contributor.author | 강혜림 | - |
dc.date.accessioned | 2017-07-19T11:17:22Z | - |
dc.date.available | 2017-07-19T11:17:22Z | - |
dc.date.issued | 2014-02 | - |
dc.identifier.other | 000000018368 | - |
dc.identifier.uri | https://hdl.handle.net/10371/133530 | - |
dc.description | 학위논문 (석사)-- 서울대학교 대학원 : 약학과, 2014. 2. 이미옥. | - |
dc.description.abstract | Interferon, gamma-inducible protein 16 (IFI16) is a member of the HIN-200 family that has been implicated in apoptosis and inflammation in breast cancer. Recently, it was reported that IFI16 forms complex with metastasis-associated protein 1 (MTA1) and class II histone deacetylases (HDACs) and the complex represses the transcription of estrogen receptor alpha (ERα). However, the role of IFI16 in breast cancer cell growth or tumor progression remains largely unknown. Therefore, we aimed to identify the effects of IFI16 on hormone-dependent proliferation and estrogen signaling in breast cancer cells. First, we established stable subline that expresses shRNA of IFI16 or MTA1 using ERα-negative breast cancer cell line, MDA-MB-231, in order to investigate the cellular growth properties according to silencing of each gene. As reported, we confirmed the increase of mRNA and protein levels of ERα by knockdown of MTA1 or IFI16 in these stable sublines. Moreover, in cell proliferation assay, clonogenic survival assay and xenograft tumor growth experiment, we verified that treatment of tamoxifen, which is an anti-hormone drug targeting ERα, significantly reduced cell growth compared with shGFP-expressing control cell. Next, we profiled the estrogen receptor (ER) signaling-related gene expression pattern using the PCR array in MDA-MB-231 after knockdown or overexpression of IFI16. Nine genes were up- or down-regulated more than 1.5-fold. Among them, induction of Cytochrome P450, Family 19, Subfamily A, Polypeptide 1 (CYP19A1 or aromatase) by IFI16 was confirmed by qPCR in ERα-positive breast cancer cell line, MCF7. We also observed that concentration of estradiol in cell culture media was increased by 1.7-fold after transfection of IFI16 when measured by enzyme immunoassay (EIA). In addition, we demonstrated that IFI16 repressed the expression of AR, which is known to competitively suppress ERα-mediated transcription. When IFI16 was overexpressed, DNA binding of AR was reduced and that of ERα was induced at the promoter region of ERα-downstream gene, pS2 or progesterone receptor (PR), followed by increase of pS2 and PR mRNA levels. Furthermore, in MCF7 cell that stably overexpresses IFI16, cell growth was stimulated consistent with the activation of estrogen signaling. Taken together, our results indicate that IFI16 induces tamoxifen resistance in ERα-negative breast cancer and activates estrogen signaling and cell proliferation via regulating expression of CYP19 and AR. This study extends understanding of the roles of IFI16 in breast cancer progression and suggests a new target for prevention and treatment of breast cancer. | - |
dc.description.tableofcontents | ABSTRACT ⅰ
CONTENTS ⅳ LIST of FIGURES ⅵ LIST of TABLES ⅶ Ⅰ. INTRODUCTION 1 Ⅱ. PURPOSE of the STUDY 8 Ⅲ. MATERIALS and METHODS 9 1. Cell culture and cell treatment 9 2. Plasmids, siRNA duplexes and transient transfection 9 3. Establishment of stable cell lines 10 4. Western blotting 10 5. Reverse transcription-polymerase chain reaction (RT-PCR) and quantitative real time PCR 11 6. Cell proliferation assay 11 7. Clonogenic survival assay 12 8. Xenograft experiment 12 9. PCR array 13 10. Estradiol EIA assay 14 11. Chromatin immunoprecipitation assay 15 12. Statistical analysis 15 Ⅳ. RESULTS 18 1. IFI16 expression in breast cancer 18 2. Loss of IFI16 or MTA1 provides susceptibility to tamoxifen-induced cell growth inhibition for ERα-negative breast cancer cells. 19 3. IFI16 regulates expression of ERα signaling-related genes 20 4. IFI16 increases estradiol level through induction of CYP19A1 20 5. IFI16 affects recruitment of AR and ERα to ERα-response element 21 6. Overexpression of IFI16 enhances proliferation of breast cancer cells 21 Ⅴ. DISCUSSION 36 REFERENCE 38 국문초록 44 | - |
dc.format | application/pdf | - |
dc.format.extent | 3274341 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | IFI16 | - |
dc.subject | ERα | - |
dc.subject | CYP19A1 | - |
dc.subject | AR | - |
dc.subject | Breast Cancer | - |
dc.subject.ddc | 615 | - |
dc.title | (The) role of interferon, gamma-inducible protein 16 in the estrogen signaling during breast cancer progression | - |
dc.title.alternative | 유방암 진행과정의 에스트로겐 신호전달에서 Interferon, gamma-inducible protein 16의 역할 규명 | - |
dc.type | Thesis | - |
dc.contributor.AlternativeAuthor | Hae-Lim Kang | - |
dc.description.degree | Master | - |
dc.citation.pages | vii, 45 | - |
dc.contributor.affiliation | 약학대학 약학과 | - |
dc.date.awarded | 2014-02 | - |
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