Breast Neoplasms: Choi Y

Jang JY, Choi Y, Jeon YK, Aung KC, Kim CW. · Department of Pathology, Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, 28 Yeongeon-dong, Jongno-gu, Seoul 110-799, South Korea. · BMC Cancer. · Pubmed #18522758 links to  free full text

Abstract: BACKGROUND: Adenine nucleotide translocase (ANT) is located in the inner mitochondrial membrane and catalyzes the exchange of mitochondrial ATP for cytosolic ADP. ANT has been known to be a major component of the permeability transition pore complex of mitochondria and contributes to mitochondria-mediated apoptosis. Human ANT has four isoforms (ANT1, ANT2, ANT3, and ANT4), and the expression of the ANT isoforms is variable depending on the tissue and cell type, developmental stage, and proliferation status. Among the isoforms, ANT1 is highly expressed in terminally-differentiated tissues, but expressed in low levels in proliferating cells, such as cancer cells. In particular, over-expression of ANT1 induces apoptosis in cultured tumor cells. METHODS: We applied an ANT1 gene transfer approach to induce apoptosis and to evaluate the anti-tumor effect of ANT1 in a nude mouse model. RESULTS: We demonstrated that ANT1 transfection induced apoptosis of MDA-MB-231 cells, inactivated NF-kappaB activity, and increased Bax expression. ANT1-inducing apoptosis was accompanied by the disruption of mitochondrial membrane potential, cytochrome c release and the activation of caspases-9 and -3. Moreover, ANT1 transfection significantly suppressed tumor growth in vivo. CONCLUSION: Our results suggest that ANT1 transfection may be a useful therapeutic modality for the treatment of cancer.

Park C, Moon DO, Ryu CH, Choi B, Lee W, Kim GY, Choi Y. · Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, Korea. · Acta Pharmacol Sin. · Pubmed #18298899 links to  free full text

Abstract: AIM: To investigate whether subtoxic concentration of beta-sitosterol (SITO) combined with TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in TRAIL-resistant MDA-MB-231 breast cancer cells. METHODS: Cell viability and growth were assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphnyl-2H-tetrazolim bromide assays, chromatin condensation, release of lactate dehydrogenase (LDH), and Annexin V+ cells. The apoptosis-related proteins were detected by Western blotting. RESULTS: Treatment with TRAIL in combination with subtoxic concentrations of SITO sensitized MDA-MB-231 breast cancer cells to TRAIL-mediated apoptosis. The synergistic treatment induced chromatin condensation, DNA fragmentation, the release of LDH, and Annexin V+ cells. The indicators of apoptosis are correlated to the induction of caspase activities, which results in the cleavage of poly(ADP-ribose)polymerase. Both the cytotoxic effects and apoptotic characteristics induced by the synergistic treatment were significantly inhibited by a pan-caspase inhibitor z-VAD-fmk, demonstrating the important role of caspases. These results indicate that caspases are crucial regulators of apoptosis induced by the combined treatment of SITO and TRAIL in MDA-MB-231 cells. CONCLUSION: The synergistic treatment of SITO and TRAIL induces apoptosis, which can serve as a potential preventive and therapeutic agent.

Jang JY, Choi Y, Jeon YK, Kim CW. · Department of Pathology, Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-dong, Jongno-gu, Seoul 110-799, South Korea. · Breast Cancer Res. · Pubmed #18267033 links to  free full text

Abstract: INTRODUCTION: Adenine nucleotide translocator (ANT) 2 is highly expressed in proliferative cells, and ANT2 induction in cancer cells is known to be directly associated with glycolytic metabolisms and carcinogenesis. In addition, ANT2 repression results in the growth arrest of human cells, implying that ANT2 is a candidate for cancer therapy based on molecular targeting. METHODS: We utilized an ANT2-specific RNA interference approach to inhibit ANT2 expression for evaluating its antitumor effect in vitro and in vivo. Specifically, to investigate the therapeutic potential of ANT2 repression, we used a DNA vector-based RNA interference approach by expressing shRNA to knockdown ANT2 in breast cancer cell lines overexpressing ANT2. RESULTS: ANT2 shRNA treatment in breast cancer cell line MDA-MB-231 repressed cell growth as well as proliferation. In addition, cell cycle arrest, ATP depletion and apoptotic cell death characterized by the potential disruption of mitochondrial membrane were observed from the ANT2 shRNA-treated breast cancer cells. Apoptotic breast cancer cells transfected with ANT2 shRNA also induced a cytotoxic bystander effect that generates necrotic cell death to the neighboring cells. The intracellular levels of TNFalpha and TNF-receptor I were increased in ANT2 shRNA transfected cells and the bystander effect was partly blocked by anti-TNFalpha antibody. Ultimately, ANT2 shRNA effectively inhibited tumor growth in vivo. CONCLUSION: These results suggest that vector-based ANT2 RNA interference could be an efficient molecular therapeutic method for breast cancer with high expression of ANT2.

Kim HM, Hong SH, Kim MS, Lee CW, Kang JS, Lee K, Park SK, Han JW, Lee HY, Choi Y, Kwon HJ, Han G. · Korea Research Institute of Bioscience and Biotechnology, Yuseong, Daejeon 305-333, Republic of Korea. · Bioorg Med Chem Lett. · Pubmed #17904843 No free full text.

Abstract: Novel delta-lactam-based HDAC inhibitors which have various substituted benzyl, bi-aromatic cap groups were prepared using ring closure metathesis reaction, and evaluated their HDAC inhibitory activities and anti-proliferative effects. Among prepared analogues, 11m and 11o have very strong HDAC enzymatic inhibition and showed the most potent growth inhibitory activity to five human tumor cell lines including PC-3, ACHN, NUGC-3, HCT-15, and MBA-MB-231 tumor cell lines. Compounds 11m and 11o also showed good tumor growth inhibition of MDA-MB-231 cells in in vivo xenograft model. Structure-activity relationship study using docking model explained the significance of hydrophobic aromatic cap groups for their in vitro activities.

Choi Y, Shimogawa H, Murakami K, Ramdas L, Zhang W, Qin J, Uesugi M. · TheVerna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. · Chem Biol. · Pubmed #16638529 No free full text.

Abstract: Insulin-like growth factor 2 (IGF2) is a potent mitogen whose deregulation plays a role in developing liver, breast, and prostate cancers. Here, we take a small-molecule approach to investigate molecular pathways that modulate IGF2 signaling, by using chromeceptin, a synthetic molecule that selectively impairs the viability and growth of IGF2-overexpressing hepatocellular carcinoma cells. Affinity purification revealed that chromeceptin binds to multifunctional protein 2 (MFP-2), a seemingly multifunctional enzyme implicated in peroxisomal beta-oxidation. The small molecule-protein interaction stimulates the expression of IGF binding protein 1 (IGFBP-1) and suppressor of cytokine signaling-3 (SOCS-3), two cellular attenuators of the IGF signals, through activation of signal transducers and activators of transcription 6 (STAT6). The results underline the importance of STATs in IGF/insulin regulation, and they implicate a new pathway for STAT6 activation that is amenable to small-molecule intervention.

Choi Y, Kim YJ, Shin HR, Noh DY, Yoo KY. · Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea. · Asian Pac J Cancer Prev. · Pubmed #15780025 No free full text.

Abstract: Not only the incidence but also the mortality of female breast cancer has been steadily increasing in Korea since the 1980s. Epidemiologic evidence on changes in lifestyle and risk factors related with breast cancer, and data from migrant studies strongly suggest that breast cancer might further increase. In order to estimate the long-term trend in mortality of breast cancer in Korean women, we analyzed age-specific mortality rates for breast cancer over the past 20 years, and made a projection up to 2020 using a linear regression model with the Poisson distribution. The age-adjusted mortality rates for breast cancer per 100,000 persons were 2.84 in 1983, 4.91 in 1993, and 6.26 in 2003. The predicted expected age-adjusted mortality rates for breast cancer are 6.51 for 2005, 7.37 for 2010, 8.22 for 2015, and 9.07 for 2020, with an estimated annual increment of breast cancer mortality of 0.1704. Accordingly, 1,564 women in 2005 and 3,087 in 2020 will be expected to die of breast cancer in Korea. Compared with the rate in 1983, this indicates a more than 3-fold increase by 2020. On the basis of our results, female breast cancer in Korea will linearly increase for the forseeable future if the trend over the past 20 years continues.

Choi Y, Pinto M. · Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. · Appl Immunohistochem Mol Morphol. · Pubmed #15722789 No free full text.

Abstract: The estrogen receptor (ER)-beta isoform has been recently identified to be distinct from ERalpha isoform and regulates separate sets of genes, and can exert opposite signaling functions depending on the ligand and response elements. Previous studies of ERbeta have been at the mRNA level and few by immunohistochemistry, and the results are inconsistent. In this study the authors compared expression of ERbeta with those of other prognostic biomarkers by immunohistochemistry on tissue microarray slides, and with morphologic parameters on 147 cases of primary breast cancer. Immunoreactivity of more than 10% of cancer cells was considered to be positive. Associations between categoric variables were analyzed using the chi test, and a P value less than 0.05 was considered to be significant. ERbeta was expressed in benign epithelium and stromal cells, and breast cancer cells in 59% of different histologic types of breast cancer. ERbeta was coexpressed with ERalpha in 45% of cases. There was a statistically significant association between expression of ERbeta and Her-2/neu (P<0.000), cathepsin D (P<0.02), p53 (P<0.03), and PS2 (P<0.002). Ki-67 was almost exclusively expressed in ERbeta-positive cells. No statistically significant association was seen between ERbeta expression and histologic grade, DNA ploidy, or S-phase.

Choe SY, Kim SJ, Kim HG, Lee JH, Choi Y, Lee H, Kim Y. · Department of Food and Nutrition, University of Ulsan, Ulsan, South Korea. · Sci Total Environ. · Pubmed #12873394 No free full text.

Abstract: We have employed an estrogen receptor dependent transcriptional expression assay and E-Screen assay systems to evaluate the estrogenicity of various heavy metals and their species. Using the former, the following estrogenicity ranking was measured: bis(tri-n-butyltin)>cadmium chloride>antimony chloride>barium chloride=chromium chloride>lithium hydroxide>sodium selenate=lead acetate>stannous chloride. Using the latter, the following estrogenicity ranking was measured: bis(tri-n-butyltin)>cadmium chloride>antimony chloride>lithium hydroxide>barium chloride>sodium selenate>chromium chloride. Especially, bis(tri-n-butyltin), cadmium chloride, antimony chloride, lithium hydroxide, barium chloride, and chromium chloride showed estrogenicity in both assay systems. Recent studies suggesting that bis(tri-n-butyltin), cadmium chloride, and lithium hydroxide have estrogenicities are compatible with the present findings. Furthermore, our studies are the first to suggest that antimony, barium, chromium may be estrogenic. A range of estrogenicity was observed for different species of the same heavy metal. The results demonstrate that an estrogen receptor dependent transcriptional expression assay and the E-Screen assay systems could serve as a useful method to assess the estrogenicity of heavy metals.

Choi Y, Park Y, Storkson JM, Pariza MW, Ntambi JM. · Department of Biochemistry, University of Wisconsin-Madison, 53706, USA. · Biochem Biophys Res Commun. · Pubmed #12061775 No free full text.

Abstract: Conjugated linoleic acid (CLA) is a collective term for a group of positional and geometric conjugated dienoic isomers of linoleic acid. CLA has been shown to have strong inhibitory effects on mammary carcinogenesis both in vitro and in vivo. In this study, we investigated the regulation of human stearoyl-CoA desaturase (SCD, EC 1.14.99.5) expression by CLA in human breast cancer cell lines, MDA-MB-231 and MCF-7. Treatment of the cells with the cis-9,trans-11 and trans-10,cis-12 CLA isomers (45 microM) did not repress SCD mRNA in both MDA-MB-231 and MCF-7 cells. However, the cis-9,trans-11 and trans-10,cis-12 CLA isomers significantly decreased SCD protein levels and SCD activity in MDA-MB-231 cells. In MCF-7 cells, both isomers did not affect protein levels, but they inhibited SCD activity. These results suggest that in MDA-MB-231 cells the cis-9,trans-11 and trans-10,cis-12 CLA isomers regulate human SCD by reducing SCD protein levels, while in MCF-7 cells both isomers have a direct inhibitory effect on SCD enzyme activity.

Kim JH, Choi Y, Joo KS, Sihn BS, Chong JW, Kim SE, Lee KH, Choe YS, Kim BT. · Department of Nuclear Medicine, Samsung Medical Center, Seoul, Korea. · Phys Med Biol. · Pubmed #11098918 No free full text.

Abstract: We have developed a small scintillation camera dedicated to breast imaging and have evaluated the performance of the system. In order to increase the limited field of view (FOV) determined by the size of a position-sensitive photomultiplier tube (PSPMT), the imaging characteristics of a diverging hole collimator (DHC) were also investigated. The small scintillation camera system consists of an NaI(Tl) crystal (60 mm x 60 mm x 6 mm) coupled to a Hamamatsu R3941 PSPMT, a resistor chain circuit, preamplifiers, nuclear instrument modules, an analogue to digital converter and a PC for control and display. The intrinsic energy resolution of the system was 12.9% FWHM at 140 keV. The spatial resolution was measured using a line-slit mask and 99mTc point sources and was 3.1 mm FWHM. The intrinsic sensitivity of the system was approximately 162 counts/s kBq(-1). The DHC made it possible to image a larger FOV (75 x 75 mm2 at the surface of collimator) than a parallel-hole collimator (60 x 60 mm2). The system sensitivity obtained using the DHC gradually decreased with distance (3% at 1 cm, 6% at 2 cm and 9% at 3 cm). The results demonstrate that the system developed in this study could be utilized clinically to image malignant breast tumours. A DHC can be employed to expand the FOV of the system confined by the size of PSPMT with a modest compromise in the performance of the system.

Choi Y, Kim Y, Park SK, Shin HR, Yoo KY. · Department of Preventive Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea. · Breast Cancer. · Pubmed #16929120 links to  free full text

Abstract: BACKGROUND: Although breast cancer in women remains relatively rare in Korea, its incidence and mortality figures are increasing, consistent with the increasing risk observed in successive generations of Korean women. The aim of the current study was to examine time trends of breast-cancer mortality during the period 1984-2003 in Korea, assessing the importance of the effects of age, period and birth cohort as risk factors. METHODS: Data on the annual number of deaths due to female breast cancer and on female population statistics from 1984 to 2003 were obtained from the Korean National Statistical Office. A log-linear Poisson age-period-cohort model was used to estimate age, period and cohort effects. RESULTS: The trend of breast cancer mortality was explained by an age-cohort model based on goodness of fit, even though the significance of the cohort effect was marginal (p=0.08) after adjusting for age. The risk of breast cancer death was found to increase with age after adjusting for the cohort effect, and it was different from the cross-sectional age curve. Also, breast cancer mortality increased along with the birth cohort. CONCLUSIONS: Even though the cohort effect was found to have a marginally significant effect on breast cancer mortality, it is expected to be more significant in the future given the recent on-going changes in diet and reproductive behavior shown by Korean women.