Amphiregulin confers trastuzumab resistance via AKT and ERK activation in HER2-positive breast cancer

Kim, Ji-Won,Kim, Debora K.,Min, Ahrum,Lee, Kyung-Hun,Nam, Hyun-Jin,Kim, Jee Hyun,Kim, Jin-Soo,Kim, Tae-Yong,Im, Seock-Ah,Park, In Ae Springer-Verlag 2016 JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY Vol.142 No.1

<P>Purpose Human epidermal growth factor receptor 2 (HER2) heterodimerizes and shares common signaling pathways with epidermal growth factor receptor (EGFR). In this study, we investigated the clinical implication of amphiregulin, a ligand for EGFR, on trastuzumab therapy in HER2-positive breast cancer. Methods Serum amphiregulin levels were quantified in 50 consecutive patients with HER2-positive metastatic breast cancer who received first-line trastuzumab plus taxane chemotherapy between October 2004 and July 2009. In addition, in vitro experiments were carried out to validate the results. Results The median serum amphiregulin level was 1.0 ng/mL with a maximum level of 4.4 ng/mL. Patients with high serum amphiregulin levels (>= 0.5 ng/mL) had significantly shorter progression-free survival (15.1 months vs. not reached; P = 0.018). Colony-forming assays demonstrated that the addition of amphiregulin resulted in increased proliferation of cells. In addition, the anti-proliferative effect of trastuzumab was decreased in the presence of amphiregulin. Western blot analysis showed that amphiregulin activated AKT and ERK pathways. In addition, in the presence of amphiregulin, sustained phosphorylation of AKT and ERK pathways was observed after trastuzumab treatment. Conclusions High serum amphiregulin levels were associated with early disease progression in these patients, possibly due to AKT and ERK signaling activation by amphiregulin.</P>

산화아연-셀룰로오스 하이브리드 나노복합재의 에너지 획득 응용

김재환(Jaehwan Kim),김현찬(Hyun Chan Kim),김정웅(Jeong Woong Kim),김드보라(Debora Kim),루스(Ruth Mangoweli) 한국소음진동공학회 2017 한국소음진동공학회 학술대회논문집 Vol.2017 No.4

AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells

Min, Ahrum,Im, Seock-Ah,Jang, Hyemin,Kim, Seongyeong,Lee, Miso,Kim, Debora Keunyoung,Yang, Yaewon,Kim, Hee-Jun,Lee, Kyung-Hun,Kim, Jin Won,Kim, Tae-Yong,Oh, Do-Youn,Brown, Jeff,Lau, Alan,O'Connor, Mar American Association for Cancer Research 2017 Molecular Cancer Therapeutics Vol.16 No.4

<P>These findings suggest synthetic lethality between ATR inhibition and ATM deficiency in gastric cancer cells. Further clinical studies on the interaction between AZD 6738 and ATM deficiency are warranted to develop novel treatment strategies for gastric cancer. (C)2017 AACR.</P>

Effect of Wet Spinning and Stretching to Enhance Mechanical Properties of Cellulose Nanofiber Filament

Hyun Chan Kim,Debora Kim,Ji Yun Lee,Lindong Zhai,Jaehwan Kim 한국정밀공학회 2019 International Journal of Precision Engineering and Vol.6 No.3

Long filament made with nanocellulose has been researched due to its eminent mechanical and physical properties for next generation of natural fiber reinforced polymer composites. Wet spinning process for long filament fabrication in conjunction with stretching method has advantages of high efficiency and low-cost. To fabricate homogeneous and strong cellulose nanofiber filament, this paper experimentally investigates the process parameters, including spinning speed, pre-dry temperature and inner diameter of needle. In addition to the spinning process, a mechanical stretching process is taken into account to further improve the mechanical properties of the cellulose nanofiber filament. The effects of wet spinning and stretching are evaluated by using scanning electron microscope, tensile test and 2D wide angle X-ray diffraction. As a result, the stretched cellulose nanofiber filament exhibits its Young’s modulus of 37.5 GPa and tensile strength of 543.1 MPa, which are significantly improved from the previous reports. All about the fabrication process, characterization and evaluation of the cellulose nanofiber filaments are illustrated.

Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), enhances anti-tumor effects of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in triple-negative breast cancer cells

Min, Ahrum,Im, Seock-Ah,Kim, Debora Keunyoung,Song, Sang-Hyun,Kim, Hee-Jun,Lee, Kyung-Hun,Kim, Tae-Yong,Han, Sae-Won,Oh, Do-Youn,Kim, Tae-You,O’Connor, Mark J,Bang, Yung-Jue BioMed Central 2015 Breast cancer research Vol.17 No.-

<P><B>Introduction</B></P><P>Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been found to have therapeutic potential for treating cancers associated with impaired DNA repair capabilities, particularly those with deficiencies in the homologous recombination repair (HRR) pathway. Histone deacetylases (HDACs) are important for enabling functional HRR of DNA by regulating the expression of HRR-related genes and promoting the accurate assembly of HRR-directed sub-nuclear foci. Thus, HDAC inhibitors have recently emerged as a therapeutic agent for treating cancer by inhibiting DNA repair. Based on this, HDAC inhibition could be predicted to enhance the anti-tumor effect of PARP inhibitors in cancer cells by blocking the HRR pathway.</P><P><B>Methods</B></P><P>We determined whether suberoylanilide hydroxamic acid (SAHA), a HDAC inhibitor, could enhance the anti-tumor effects of olaparib on breast cancer cell lines using a cytotoxic assay, cell cycle analysis, and Western blotting. We evaluated how exposure to SAHA affects the expression of HRR-associated genes. The accumulation of DNA double strand breaks (DSBs) induced by combination treatment was assessed. Induction of autophagy was monitored by imaging green fluorescent protein-tagged microtubule-associated protein 1A/1B-light chain 3 (LC3) expression following co-treatment with olaparib and SAHA. These <I>in vitro</I> data were validated <I>in vivo</I> using a human breast cancer xenograft model.</P><P><B>Results</B></P><P>Triple-negative breast cancer cell (TNBC) lines showed heterogeneous responses to the PARP and HDAC inhibitors. Co-administration of olaparib and SAHA synergistically inhibited the growth of TNBC cells that expressed functional Phosphatase and tensin homolog (PTEN). This effect was associated with down-regulation of the proliferative signaling pathway, increased apoptotic and autophagic cell death, and accumulation of DNA damage. The combined anti-tumor effect of olaparib and SAHA was also observed in a xenograft model. These data suggest that PTEN expression in TNBC cells can sensitize the cell response to simultaneous inhibition of PARP and HDAC both <I>in vitro</I> and <I>in vivo</I>.</P><P><B>Conclusion</B></P><P>Our findings suggest that expression of functional PTEN may serve as a biomarker for selecting TNBC patients that would favorably respond to a combination of olaparib with SAHA. This provides a strong rationale for treating TNBC patients with PTEN expression with a combination therapy consisting of olaparib and SAHA.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1186/s13058-015-0534-y) contains supplementary material, which is available to authorized users.</P>

기계적 연신에 의한 전기활성 셀룰로오스 필름의 주름패턴에 대한 유한요소 해석

윤선진(Seanjhin Yoon),김정웅(Jung Woong Kim),윤영민(Youngmin Yun),김드보라(Debora Kim),김재환(Jaehwan Kim) 대한기계학회 2018 大韓機械學會論文集A Vol.42 No.5

인장 변형률, 횡방향 변형률, 부정합 각도를 고려한 기계적 연신이 전기활성 셀룰로오스 필름의 주름패턴에 미치는 영향을 유한요소해석을 수행하였다. 횡방향 변형률이 고정된 상태에서 인장 변형률이 증가하는 경우, 초기에는 작은 면외 변위를 가지는 주름들이 보여지다가 이후 파장이 감소하면서 완전히 발달된 주름들이 필름 전반에 분포하였다. 이어서 횡방향 변형률을 증가시키는 경우, 강한 휨의 영향으로 주름의 파장이 오히려 증가하는 것을 보여 주었다. 부정합 각도가 고정된 상태에서 인장 변형률이 증가하는 경우, 초기 경사진 주름들이 나타났으나, 이후 주름의 크기도 같이 증가하는 것을 볼 수 있었다. 또한 이어서 부정합 각도를 증가시키는 경우, 작은 주름, 국소적으로 분포 주름, 완전히 발달된 주름이 순차적으로 발견되었다. A finite element analysis is presented to investigate wrinkle patterns in electroactive cellulose films, which were induced by mechanical stretching with tensile strain, lateral strain, and misalignment angle. As the tensile strain increased with a constant lateral stain, electroactive cellulose film showed weak wrinkles with low magnitudes in the beginning and, thereafter, fully-developed wrinkles with the wavelength decreased. As the lateral strain increased with a constant tensile stain, the wavelength of wrinkles increased because of the strong effect of bending. Contrarily, as the tensile strain increased with a constant misalignment angle, electroactive cellulose film showed inclined wrinkles in all of the cases. As the magnitude of the wrinkles increased along with the tensile strain. As the misalignment angle increased with a constant tensile stain, three types of wrinkles- small, locally-distributed, fully-developed wrinkles-were observed in order.

Conjugated Linoleic Acid Reduction of Vascular Endothelial Growth Factor Expression in Murine Mammary Tumor Cells through Alteration of Prostaglandin E₂

Kim, Jung-Hyun,Hubbard, Neil E.,Lim, Debora,Erickson, Kent L. The Korean Society of Food Science and Nutrition 2006 Preventive Nutrition and Food Science Vol.11 No.1

Conjugated linoleic acid (CLA) is a group of positional and geometric isomers of linoleic acid that have been used to reduce the incidence, growth and metastasis of breast, colon, prostate and gastric cancer in animals. CLA could reduce tumor growth by altering angiogenesis; a process requiring associated angiogenic factors such as vascular endothelial growth factor (VEGF). In this study, we determined whether CLA could modulate the expression of VEGF in murine mammary tumor cells and adipocytes. The c9, t11-CLA isomer reduced VEGF transcripts and protein when mammary tumor cells were stimulated with PMA. That isomer also reduced VEGF expression in un stimulated mouse 3T3-L1 adipocytes. Since VEGF can be regulated by cyclooxygenase-2 (COX-2), we determined whether CLA could alter COX-2 enzyme expression and $PGE_2$ production. The c9, t11-CLA isomer reduced not only COX-2 enzyme expression but also $PGE_2$ production. Thus, c9, t11-CLA could modulate neovascularization by alteration of VEGF expression from mammary tumor cells and adipocytes by reducing COX-2 metabolites.

Investigation of the efficacy of mycotoxin-detoxifying additive on health and growth of newly-weaned pigs under deoxynivalenol challenges

Holanda Debora Muratori,Kim Sung Woo 아세아·태평양축산학회 2021 Animal Bioscience Vol.34 No.3

Objective: This study evaluated the effects of feeding diets naturally contaminated with deoxynivalenol (supplemental 2 mg/kg) on health, growth, and the effects of a mycotoxindetoxifying additive in newly-weaned pigs.Methods: Thirty-six pigs (27 day-old) were housed individually and assigned to 3 treatments for 5 weeks: CON (diet containing minimal deoxynivalenol), MT (diet with supplemental 1.9 mg/kg of deoxynivalenol), and MT+D (MT + mycotoxin-detoxifying additive, 0.2%, MegaFix, ICC, São Paulo, Brazil). The mycotoxin-detoxifying additive included bentonite, algae, enzymes, and yeast. Blood was taken at week 2 and 5. Jejunal tissue were taken at week 5. Data were analyzed using the MIXED procedure of SAS.Results: Pigs fed MT+D tended to have decreased (p = 0.056) averaged daily feed intake during week 1 than MT. At week 2, serum aspartate aminotransferase/alanine aminotransferase in MT tended to be lower (p = 0.059) than CON, whereas it was increased (p< 0.05) for MT+D than MT, indicating hepatic damages in MT and recovery in MT+D. Pigs fed MT had lower (p<0.05) blood urea nitrogen/creatinine than CON, supporting hepatic damage. At week 5, pigs fed MT tended to have reduced (p = 0.079) glucose than CON, whereas it was increased (p<0.05) for MT+D than MT, indicating impaired intestinal glucose absorption in MT, which was improved in MT+D. Pigs fed CON tended to have increased (p = 0.057) total glutathione in jejunum than MT, indicating oxidative stress in MT. Pigs fed MT+D had a reduced (p<0.05) proportion of Ki-67-positive cells in jejunum than MT, indicating lower enterocyte proliferation in MT+D.Conclusion: Feeding supplemental 1.9 mg/kg of deoxynivalenol reduced growth and debilitated hepatic health of pigs, as seen in leakage of hepatic enzymes, impaired nitrogen metabolism, and increase in oxidative stress. The mycotoxin-detoxifying enhanced hepatic health and glucose levels, and attenuated gut damage in pigs fed deoxynivalenol contaminated diets. Objective: This study evaluated the effects of feeding diets naturally contaminated with deoxynivalenol (supplemental 2 mg/kg) on health, growth, and the effects of a mycotoxindetoxifying additive in newly-weaned pigs. Methods: Thirty-six pigs (27 day-old) were housed individually and assigned to 3 treatments for 5 weeks: CON (diet containing minimal deoxynivalenol), MT (diet with supplemental 1.9 mg/kg of deoxynivalenol), and MT+D (MT + mycotoxin-detoxifying additive, 0.2%, MegaFix, ICC, São Paulo, Brazil). The mycotoxin-detoxifying additive included bentonite, algae, enzymes, and yeast. Blood was taken at week 2 and 5. Jejunal tissue were taken at week 5. Data were analyzed using the MIXED procedure of SAS. Results: Pigs fed MT+D tended to have decreased (p = 0.056) averaged daily feed intake during week 1 than MT. At week 2, serum aspartate aminotransferase/alanine aminotransferase in MT tended to be lower (p = 0.059) than CON, whereas it was increased (p< 0.05) for MT+D than MT, indicating hepatic damages in MT and recovery in MT+D. Pigs fed MT had lower (p<0.05) blood urea nitrogen/creatinine than CON, supporting hepatic damage. At week 5, pigs fed MT tended to have reduced (p = 0.079) glucose than CON, whereas it was increased (p<0.05) for MT+D than MT, indicating impaired intestinal glucose absorption in MT, which was improved in MT+D. Pigs fed CON tended to have increased (p = 0.057) total glutathione in jejunum than MT, indicating oxidative stress in MT. Pigs fed MT+D had a reduced (p<0.05) proportion of Ki-67-positive cells in jejunum than MT, indicating lower enterocyte proliferation in MT+D. Conclusion: Feeding supplemental 1.9 mg/kg of deoxynivalenol reduced growth and debilitated hepatic health of pigs, as seen in leakage of hepatic enzymes, impaired nitrogen metabolism, and increase in oxidative stress. The mycotoxin-detoxifying enhanced hepatic health and glucose levels, and attenuated gut damage in pigs fed deoxynivalenol contaminated diets.

Conjugated Linoleic Acid Reduction of Vascular Endothelial Growth Factor Expression in Murine Mammary Tumor Cells through Alteration of Prostaglandin E₂

Jung-Hyun Kim,Neil E. Hubbard,Debora Lim,Kent L. Erickson 한국식품영양과학회 2006 Preventive Nutrition and Food Science Vol.11 No.1

Conjugated linoleic acid (CLA) is a group of positional and geometric isomers of linoleic acid that have been used to reduce the incidence, growth and metastasis of breast, colon, prostate and gastric cancer in animals. CLA could reduce tumor growth by altering angiogenesis; a process requiring associated angiogenic factors such as vascular endothelial growth factor (VEGF). In this study, we determined whether CLA could modulate the expression of VEGF in murine mammary tumor cells and adipocytes. The c9, t11-CLA isomer reduced VEGF transcripts and protein when mammary tumor cells were stimulated with PMA. That isomer also reduced VEGF expression in unstimulated mouse 3T3-L1 adipocytes. Since VEGF can be regulated by cyclooxygenase-2 (COX-2), we determined whether CLA could alter COX-2 enzyme expression and PGE₂ production. The c9, t11-CLA isomer reduced not only COX-2 enzyme expression but also PGE₂ production. Thus, c9, t11-CLA could modulate neovascularization by alteration of VEGF expression from mammary tumor cells and adipocytes by reducing COX-2 metabolites.

Androgen Receptor Inhibitor Enhances the Antitumor Effect of PARP Inhibitor in Breast Cancer Cells by Modulating DNA Damage Response

Min, Ahrum,Jang, Hyemin,Kim, Seongyeong,Lee, Kyung-Hun,Kim, Debora Keunyoung,Suh, Koung Jin,Yang, Yaewon,Elvin, Paul,O'Connor, Mark J.,Im, Seock-Ah American Association for Cancer Research 2018 Molecular cancer therapeutics Vol.17 No.12

<P>The androgen receptor (AR) is expressed in 60%–70% of breast cancers regardless of estrogen receptor status, and has been proposed as a therapeutic target in breast cancers that retain AR. In this study, the authors aimed to investigate a new treatment strategy using a novel AR inhibitor AZD3514 in breast cancer. AZD3514 alone had a minimal antiproliferative effect on most breast cancer cell lines irrespective of AR expression level, but it downregulated the expressions of DNA damage response (DDR) molecules, including ATM and chk2, which resulted in the accumulation of damaged DNA in some breast cancer cells. Furthermore, AZD3514 enhanced cellular sensitivity to a PARP inhibitor olaparib by blocking the DDR pathway in breast cancer cells. Furthermore, the downregulation of NKX3.1 expression in MDA-MB-468 cells by AZD3514 occurred in parallel with the suppression of ATM–chk2 axis activation, and the suppression of NKX3.1 by AZD3514 was found to result from AZD3514-induced TOPORS upregulation and a resultant increase in NKX3.1 degradation. The study shows posttranslational regulation of NKX3.1 via TOPORS upregulation by AZD3514-induced ATM inactivation–increased olaparib sensitivity in AR-positive and TOPORS-expressing breast cancer cells, and suggests the antitumor effect of AZD3514/olaparib cotreatment is caused by compromised DDR activity in breast cancer cell lines and in a xenograft model. These results provide a rationale for future clinical trials of olaparib/AR inhibitor combination treatment in breast cancer.</P>