• 한국발생생물학회지:발생과생식
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• 제6권2호
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• pp.117-122
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• 2002

포유동물에서 뇌와 부신에서 합성ㆍ분비되는 카테콜아민(Catecholamine, CA)계 신경전달물질인 dopamine(DA), norepinephrine(NE), epinephrine(E)은 체내 각종 생리현상의 조절에 필수적이며, 생식과 관련된 기능으로는 시상하부와 뇌하수체 사이의 GnRH-gonadotropin 호르몬 축의 활성을 조절함 외에도 번식과 연관된 여러 행동양식을 조절함이 잘 알려져 있다. 본 연구는 카테콜아민 생합성 효소인 tyrosine hydroxylase(TH), dopamine $\beta$ -hydroxylase(DBH), phenylethaolamine-N-methyl transferase(PNMT)의 유전자 발현에 영향을 미치는 sex steroid의 영향을 조사하였다. 성숙한 암컷 흰쥐의 난소를 제거(ovariectomy, OVX)하고 1주 경과 후 실험군과 대조군에 각각 17$\beta$-estradiol(E$_2$; 500$\mu\textrm{g}$/m1)이 들어 있는 silastic capsule과 sesame oil이 들어 있는 silastic capsule을 이식시키고 48시간 후에 희생시켰다. 채취된 조직에서 mRNA를 추출한 후 semi-quantitative reverse transcription-polymerase chain reaction(RT-PCR)을 시행하였다. 그 결과로 (i) TH의 발현 정도는 OVX＋Oil군에서는 시상하부 > Substantia nigra(SNc) > 부신 순으로, OVX＋E$_2$군에서는 SNc ) 시상하부 > 부신 순으로 나타났다. TH발현에 미치는 estradiol의 효과로 SNc와 부신에서는 유의한 증가를 보인데 비해 시상하부에서는 유의한 감소를 관찰하였다. (ⅱ) DBH 발현 정도는 OVX＋Oil군과 OVXi＋E$_2$군에서 모두 부신 > SNc > 시상하부 순으로 나타났다. DBH 발현에 미치는 estradiol의 효과로 SNc에서는 유의한 감소를, 부신에서는 유의한 증가를, 그리고 시상하부에서는 감소하였으나 통계적 유의성이 없었다. (ⅲ) PNMT의 발현의 경우 SNc와 시상하부에서는 이미 알려진 바와 같이 alternative splicing에 의해 110bp 차이의 크고 작은 두 형태의 cDNA(PNMT과 PNMTSs가 증폭되었으나 부신에서는 작은 cDNA(PNMTs)만이 관찰되었다. PNMT1의 발현은 SNc가 시상하부보다 다소 높은 경향이었으나 유의성이 없었고, PNMTs의 발현정도는 OVX＋Oil군과 OVX＋E$_2$군 모두에서 부신 > SNC >시상하부 순으로 나타났다. PNMTs 발현에 미치는 estradiol의 효과로 SNc에서는 유의한 감소를, 부신에서는 유의한 증가를, 그리고 시상하부에서는 통계적 유의성은 없으나 증가하는 경향을 보였다. 본 연구에서는 카테콜아민 생합성 효소들의 유전자 발현의 조절에 미치는 estrogen의 영향이 세포기원이 neural crest cell인 부신 수질은 물론 뇌의 상이한 지역간에서도 조직특이적임을 관찰하였다. 이러한 결과는 각 조직에서의 estrogen 수용체 유형의 차이, 작용 모드와 각 효소 유전자 발현 사이에 중요한 상관관계가 있음을 시사한다.

• Genomics & Informatics
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• 제21권2호
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• pp.20.1-20.10
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• 2023

Aromatase inhibitors (AI) are drugs that are widely used in treating estrogen receptor (ER)-positive breast cancer patients. Drug resistance is a major obstacle to aromatase inhibition therapy. There are diverse reasons behind acquired AI resistance. This study aims at identifying the plausible cause of acquired AI resistance in patients administered with non-steroidal AIs (anastrozole and letrozole). We used genomic, transcriptomic, epigenetic, and mutation data of breast invasive carcinoma from The Cancer Genomic Atlas database. The data was then separated into sensitive and resistant sets based on patients' responsiveness to the non-steroidal AIs. A sensitive set of 150 patients and a resistant set of 172 patients were included for the study. These data were collectively analyzed to probe into the factors that might be responsible for AI resistance. We identified 17 differentially regulated genes (DEGs) among the two groups. Then, methylation, mutation, miRNA, copy number variation, and pathway analyses were performed for these DEGs. The top mutated genes (FGFR3, CDKN2A, RNF208, MAPK4, MAPK15, HSD3B1, CRYBB2, CDC20B, TP53TG5, and MAPK8IP3) were predicted. We also identified a key miRNA - hsa-mir-1264 regulating the expression of CDC20B. Pathway analysis revealed HSD3B1 to be involved in estrogen biosynthesis. This study reveals the involvement of key genes that might be associated with the development of AI resistance in ER-positive breast cancers and hence may act as a potential prognostic and diagnostic biomarker for these patients.

• Clinical and Experimental Reproductive Medicine
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• 제30권4호
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• pp.309-316
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• 2003

연구목적: 스테로이드 계통의 에스트로겐 호르몬은 막 수용체와 결합하고 DNA에 부착되어, 자궁조직에서 발현되는 많은 유전자들의 발현 양상을 조절하는 것으로 알려져 있다. 본 연구에서는 난소를 제거한 생쥐 모델을 이용하여 에스트로겐에 의해 조절되는 전사 관련 유전자(transcription factor)들을 동정하고, early up-regulation gene으로 확인된 Fos related antigen (Fra1과 Fra2) 유전자의 발현 양상을 RT-PCR과 면역염색방법으로 살펴보았다. 연구재료 및 방법: 난소 절제술을 시행한 생쥐에 에스트로겐을 피하주사하고 2, 4, 6, 12시간 간격으로 자궁조직을 적출하였다. 대조군으로는 sesame oil만을 주사한 후 2시간째에 수획한 자궁조직을 사용하였으며, 시간대별로 채취한 자궁조직(n=4)에서 RT-PCR을 수행하였다. RT-PCR을 통해 early response gene으로 확인된 Fra1과 Fra2에 대한 에스트로겐의 영향을 살펴보기 위해 estrogen receptor antagonist인 ICI 182, 780을 주사하여 유전자 발현 양상의 변화를 살펴보았다. 또한, 자궁조직내에서의 단백질 발현 부위를 관찰하기 위해 면역조직화학염색을 실시하였다. 결 과: 생쥐 자궁조직에서 에스트로겐에 의해 발현 양상의 변화가 확인된 유전자는 early up-regulation genes (CREB2, Fra-1, 2, GATA5), late up-regulation gene (E2F1), no response genes (CREB1, ATF1, GLI3, E2F3), down-regulation genes (GLI2, E2F5, GATA-2, 3, 6) 등으로 구분할 수 있었다. 그 중 early up-regulation genes에 해당하는 Fra1과 Fra2 유전자는 ICI 182, 780에 의해 그 발현이 유의하게 감소되는 것을 확인하였다(p < 0.01). 이들 단백질은 생쥐 자궁조직의 상피세포층, 기질층, 근육층에서 고루 발현되었으며, 특히 근육층에서 강한 염색정도를 관찰할 수 있었다. 결 론: 이상의 결과를 통해 Fra1과 Fra2 유전자의 발현은 에스트로겐에 의해 조절됨을 알 수 있었으며, 이들의 강한 발현이 자궁조직의 근육층에서 관찰되어 이들의 기능에 대한 연구가 필요할 것으로 생각된다.

• 대한수의학회지
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• 제41권4호
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• pp.549-555
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• 2001

Indole-3-carbinol (I3C), one component of cruciferous vegetables (the Fammily of Cruciferae), has been shown to exert its chemopreventive effect in liver, colon and mammary tissue before or concurrent exposure of carcinogen, but there have been several evidences that consumption of I3C induced tumor promotion in some tissues. Our studies were investigated to examine the modifying effects of I3C in the 7,12-dimethylbenz[$\alpha$]anthracene (DMBA) induced rat mammary gland tumor model. Fifty-two female Sprague-Dawley rats were randomly divided into five groups. Animals of the group 1 were given the diet containing 100ppm I3C and animals of the groups 2 and 4 were given the diet containing 300ppm I3C from 6 weeks of age. At 7 weeks of age, the animals of the groups 1, 2 and 3 were intubated with DMBA. All amimals were killed at 20 weeks after carcinogen treatment. There were significant increases of food consumption in I3C feeding groups compared with those of basal diet feeding groups. The incidences of the mammary tumors in the group 1, 2 and 3 were 75.0% (9/12), 56.3% (9/16) and 93.8% (15/16), respectively and the average number of tumors of group 1 (DMBA+I3C 100ppm: $2.08{\pm}0.61$) and 2 (DMBA+I3C 300ppm: $1.19{\pm}0.32$) were significantly lower than that of group 3 (DMBA alone: $4.63{\pm}0.72$) at the value of P<0.05 and P<0.001, respectively. In the pathological examination of appearing tumors, most of them were adenocarcinoma. Many epithelial cells of tumors showed strong estrogen receptor (ER) $\alpha$ expression but there were slight difference of ER $\alpha$ expression among the type of tumors. We suggest that pre-initiation treatment of I3C has an inhibitory effects on mammary carcinogenesis induced by DMBA.

• 상하수도학회지
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• 제19권1호
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• pp.98-105
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• 2005

The effects of chlorination on the elimination of three estrogenic chemicals such as $17{\beta}$-estradiol (E2), nonylphenol (NP) and bis-phenol A (BPA) were investigated using yeast two-hybrid assay (YTA), estrogen receptor competition assay (ER-CA), and high-performance liquid chromatography/mass spectrometer (LC/MS). Results of YTA, ECA and the analysis of LC/MS indicated that the estrogenic activity of above mentioned three endocrine disruptors were significantly reduced as the result of chlorination. The decrease in estrogenic activity paralleled with decrease in estrogenic chemicals under the influence of free chlorine. One common characteristic of estrogenic chemicals is the presence of a phenolic ring. Considering that a phenolic ring is likely to undergo some sort of transformation in aqueous chlorination solution, the above mentioned results may be applied to the rest of the other estrogenic chemicals in natural waters.

• Journal of Chest Surgery
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• 제34권5호
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• pp.422-425
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• 2001

We performed thoracoscopic resection for diagnosis in 41 year-old-female presenting with multiple pulmonary nodules in both lung fields, which was detected incidentally on routine chest x-ray and followed by additional exmaminations including chest CT scan and percutaneous needle aspiration biopsy under the presumptive diagnosis of metastatic cancer. During thoracoscopy, the result of the frozen section analysis of multiple masses revealed strong evidence of leiomyoma. In her past medical history, she had undergone myomectomy, and hysterectomy, 7 year ago and 10 year ago, respectively. Based on permanent, special staining of specimen, estrogen receptor assay and review of past specimen of uterine myoma the final diagnosis was benign metastasizing leiomyomata from uterine myoma, the report was very uncommon in Korean and English literatures. The patient has been followed up for 2 year without special therapy, such as hormonal therapy.

• 한국발생생물학회지:발생과생식
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• 제26권2호
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• pp.49-58
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• 2022

The differentiation and development of preadipocyte into mature adipocyte are regulated by transcription factors, such as CCAAT enhancer binding protein (Cebp) gene family and sterol regulatory element binding transcription factor 1 (Srebp1). Steroid hormones give influences on the development and function of adipocyte. The present research examined expression patterns of CCAAT enhancer binding protein alpha (Cebpa), CCAAT enhancer binding protein beta (Cebpb), CCAAT enhancer binding protein gamma (Cebpg), sterol regulatory element binding transcription factor 1 (Srebp1), androgen receptor (Ar), and estrogen receptors (Esr) among different epididymal fat parts during postnatal period by quantitative real-time polymerase chain reaction. In the distal epididymal fat, expression of Cebpa, Cebpb, Cebpg, Srebp1, Ar, and Esr2 was increased until 12 months of age, while expression of Esr1 was decreased at 5 months of age and was not detectable after 8 months of age. In the proximal epididymal fat, transcript levels of Cebps and Srebp1 were increased at 8 months of age, followed by decreases of Cebpb and Cebpg transcript levels at 12 months of age. An additional increase of Srebp1 expression was observed at 12 months of age. Expression of Ar and Esr2 were increased until 8 months of age, followed by a drop of Ar expression level at 12 months of age. Expression pattern of Esr1 was similar to that in the distal epididymal fat. In the tail epididymal fat, expression of Cebpa, Cebpg, Srebp1, Ar, and Esr2 was increased with age. Esr1 was not detectable at all. The highest level of Cebpb was observed at 8 months of age. These data suggest the possibility of developmental and functional differentiation among the epididymal fat parts.

• Asian Pacific Journal of Cancer Prevention
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• 제15권19호
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• pp.8441-8445
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• 2014

Background: Paired-like homeodomain transcription factor 2 (PITX2) is another new marker in breast carcinoma since hypermethylation at P2 promoter of this gene was noted to be associated with poor prognosis. We investigated the expression of PITX2 protein using immunohistochemistry in invasive ductal carcinoma and its association with the established growth receptors such as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth receptor 2 (HER2). Methods: We conducted a cross sectional study using 100 samples of archived formalin-fixed paraffin embedded tissue blocks of invasive ductal carcinoma and stained them with immunohistochemistry for PITX2, ER, PR and HER2. All HER2 with scoring of 2+ were confirmed with chromogenic in-situ hybridization (CISH). Results: PITX2 protein was expressed in 53% of invasive ductal carcinoma and lack of PITX2 expression in 47%. Univariate analysis revealed a significant association between PITX2 expression with PR (p=0.001), ER (p=0.006), gland formation (p=0.044) and marginal association with molecular subtypes of breast carcinoma (p=0.051). Combined ER and PR expression with PITX2 was also significantly associated (p=0.003) especially in double positive cases. Multivariate analysis showed the most significant association between PITX2 and PR (RR 4.105, 95% CI 1.765-9.547, p=0.001). Conclusion: PITX2 is another potential prognostic marker in breast carcinoma adding significant information to established prognostic factors of ER and PR. The expression of PITX2 together with PR may carry a very good prognosis.

• Asian Pacific Journal of Cancer Prevention
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• 제16권12호
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• pp.4863-4867
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• 2015

Background: Triple negative breast cancer (TNBC), characterized as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 Her2 negative and accounting for 10-17% of all breast carcinomas, is only partially responsive to chemotherapy and suffers from a lack of clinically established targeted therapies. The aim of the current study was to evaluate the patterns of treatment and clinicopathology figures in Kurdish patients with triple-negative breast cancer, and to compare these to other reports. Materials and Methods: Between 2001 and 2014, 950 breast cancer patients were referred to our clinic. There were 74 female patients with TNBC, including 70 patients was invasive ductal carcinoma entered into our study. ER and PR positivity was defined as positive immunohistochemical staining in more than 10% of tumor cells. Immunohistochemistry assay with anti-HER2 antibodies was used to identify HER negative (0 and 1+) or positive (2+ and 3+). HER2 gene amplification was determined by fluorescent in situ hybridization (FISH). Overall survival (OS) was plotted with GraphPad Prism 5 Software using Kaplan-Meier and log-rank tests for comparison of results. Results: The mean age in the first diagnosis for 70 patients with triple TNBC and invasive ductal carcinoma was 49.6 years that range of age was 27-82 years. All of the patients were female. Of 70 patients, 23 patients had metastasis. Thirty-two patients (45.7%) were treated with tamoxifen and 39 (55.7%) with radiotherapy. Three-year, 5-year and 10-year OS rates for all patients were 82%, 72% and 64%, respectively. Conclusions: The OS in our West Iran TNBC patients is less than reported elsewhere. However, treatment with combination of tamoxifen plus radiation increases the OS and reduces the mortality rate.

• Journal of Microbiology and Biotechnology
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• 제32권3호
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• pp.365-377
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• 2022

Mammalian target of rapamycin (mTOR) is a serine-threonine kinase member of the cellular phosphatidylinositol 3-kinase (PI3K) pathway, which is involved in multiple biological functions by transcriptional and translational control. mTOR is a downstream mediator in the PI3K/Akt signaling pathway and plays a critical role in cell survival. In cancer, this pathway can be activated by membrane receptors, including the HER (or ErbB) family of growth factor receptors, the insulin-like growth factor receptor, and the estrogen receptor. In the present work, we congregated an electronic network of mTORC1 built on an assembly of data using natural language processing, consisting of 470 edges (activations/interactions and/or inhibitions) and 206 nodes representing genes/proteins, using the Cytoscape 3.6.0 editor and its plugins for analysis. The experimental design included the extraction of gene expression data related to five distinct types of cancers, namely, pancreatic ductal adenocarcinoma, hepatic cirrhosis, cervical cancer, glioblastoma, and anaplastic thyroid cancer from Gene Expression Omnibus (NCBI GEO) followed by pre-processing and normalization of the data using R & Bioconductor. ExprEssence plugin was used for network condensation to identify differentially expressed genes across the gene expression samples. Gene Ontology (GO) analysis was performed to find out the over-represented GO terms in the network. In addition, pathway enrichment and functional module analysis of the protein-protein interaction (PPI) network were also conducted. Our results indicated NOTCH1, NOTCH3, FLCN, SOD1, SOD2, NF1, and TLR4 as upregulated proteins in different cancer types highlighting their role in cancer progression. The MCODE analysis identified gene clusters for each cancer type with MYC, PCNA, PARP1, IDH1, FGF10, PTEN, and CCND1 as hub genes with high connectivity. MYC for cervical cancer, IDH1 for hepatic cirrhosis, MGMT for glioblastoma and CCND1 for anaplastic thyroid cancer were identified as genes with prognostic importance using survival analysis.