• Asian Pacific Journal of Cancer Prevention
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• v.15 no.24
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• pp.10577-10583
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• 2015

Background: Triple-negative breast cancer (TNBC), characterized by the lack of expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2, is typically associated with a poor prognosis. The majority of TNBCs show the expression of basal markers on gene expression profiling and most authors accept TNBC as basal-like (BL) breast cancer. However, a smaller fraction lacks a BL phenotype despite being TNBC. The literature is silent on non-basal-like (NBL) type of TNBC. The present study was aimed at defining behavioral differences between BL and NBL phenotypes. Objectives: i) Identify the TNBCs and categorize them into BL and NBL breast cancer. ii) Examine the behavioral differences between two subtypes. iii) Observe the pattern of treatment failure among TNBCs. Materials and Methods: All TNBC cases during January 2009-December 2010 were retrieved. The subjects fitting the inclusion criteria of study were differentiated into BL and NBL phenotypes using surrogate immunohistochemistry with three basal markers $34{\beta}E12$, c-Kit and EGFR as per the algorithm defined by Nielsen et al. The detailed data of subjects were collated from clinical records. The comparison of clinicopathological features between two subgroups was done using statistical analyses. The pattern of treatment failure along with its association with prognostic factors was assessed. Results: TNBC constituted 18% of breast cancer cases considered in the study. The BL and NBL subtypes accounted for 81% and 19% respectively of the TNBC group. No statistically significant association was seen between prognostic parameters and two phenotypes. Among patients with treatment failure, 19% were with BL and 15% were with NBL phenotype. The mean disease free survival (DFS) in groups BL and NBL was 30.0 and 37.9 months respectively, while mean overall survival (OS) was 31.93 and 38.5 months respectively. Treatment failure was significantly associated with stage (p=.023) among prognostic factors. Conclusions: Disease stage at presentation is an important prognostic factor influencing the treatment failure and survival among TNBCs. Increasing tumor size is related to lymph node positivity. BL tumors have a more aggressive clinical course than that of NBL as shown by shorter DFS and OS, despite having no statistically significant difference between prognostic parameters. New therapeutic alternatives should be explored for patients with this subtype of breast cancer.

• Clinical and Experimental Reproductive Medicine
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• v.31 no.4
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• pp.217-223
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• 2004

Objective: To evaluate the effects of recombinant FSH (rFSH) and urinary FSH (uFSH) on the gene expressions of human endometrial stromal cells in vitro. Methods: Endometrial tissue was obtained from a pre-menopausal women undergoing hysterectomy. Primary endometrial stromal cells were isolated and in vitro cultured with FBS-free DMEM/F-12 containing 0, 10, 100, and 1, 000 mIU/ml of rFSH and uFSH for 48 hours, respectively. Total RNA was extracted from the cultured cells and subjected to real time RT-PCR for the quantitative analysis of progesterone receptor (PR), estrogen receptor $\alpha/\beta$ (ER-$\alpha/\beta$), cyclooxygenase 2 (Cox-2), leukemia inhibitory factor (LIF), homeobox A10-1 and -2 (HoxA10-1/-2). Results: Both hormone treatments slightly increased (< 3 folds) the expressions of PR, ER-$\beta$ and HoxA10-1/-2 gene. However, ER-$\alpha$ expression was increased up to five folds by treatments of both FSH for 48 hours. The LIF expression by the 10 mIU/ml of uFSH for 12 hours was significantly higher than that of rFSH (p<0.01). After 24 hours treatment of two kinds of hormones, the expression patterns of LIF were similar. The 100 and 1, 000 mIU/ml of rFSH induced significantly higher amount of Cox-2 expression than those of uFSH, respectively (p<0.05). Conclusion: This study represents no adversely effect of exogeneous gonadotropins, rFSH and uFSH, on the expression of implantation related genes. We suggest that rFSH is applicable for the assisted reproductive technology without any concern on the endometrial receptivity.

• Journal of Food Hygiene and Safety
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• v.21 no.2
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• pp.100-106
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• 2006

The use of underarm and body care cosmetics with oestrogenic chemical excipients (particularly the parabens) and the hypothesized association with breast cancer incidence, particularly in women. It is noted that the type of cosmetic product is irrelevant (e.g. antiperspirant/deodorant versus body lotion, moisturizers or sprays versus creams) and attention must focus on issues of actual exposure to chemicals through continued dermal application of body care products and the endocrine/hormonal activity and toxicity of the chemicals in the formulations. To evaluate the estrogenic activities of parabens such as ethylparaben, butylparaben, propylparaben, isobutylparaben and isopropylparaben, we used recombinant yeasts containing the human estrogen receptor [Saccharomyces cerevisiae ER+LYS 8127], human breast cancer MCF-7 cell lines and human estrogen receptor ${\alpha}\;and\;{\beta}$. In E-screen assays, isopropylparaben is the most estrogenic paraben, and in ER competition assay, isobutylparaben is the most estrogenic paraben. We evaluated isopropylparaben was most active in the recombinant yeast assay, followed by propylparaben, ethylparaben, isobutylparaben and butylparaben. Results from this study demonstrate that parabens are observed in human endocrine system. Therefore, we have shown that the parabens is induced the estrogenic activities similar to $17{\beta}$-estradiol and Bisphenol-A.

• Development and Reproduction
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• v.10 no.4
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• pp.255-261
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• 2006

Although some phytoes rogens might have beneficiary rather than adverse effects, most endocrine disrupting compounds(EDCs) are considered to be harmful to human and wildlife health through interfering the endocrine system. Previously we found that prepubertal exposure to genistein(GS), a well-known isoflavone phytoestrogen, could activate the reproductive system of immature female rats resulting precocious puberty. Interestingly, di(2-ethyl hexyl) phthalate(DEHP) exposure brought inverse result, a delayed puberty, in the same experimental regimen. In this study, we examined whether prepubertal exposure to GS or DEHP affect the gene expressions of estrogen receptors($ER\;{\alpha}$ and $ER\;{\beta}$) and LH receptor(LHR) which represent the maturational status of ovary and uterus in immature rats. GS (100 mg/kg/day) was administered daily from postnatal day 25 to the day when the first vaginal opening(VO) was observed, and the animals were sacrificed on the next day(day 32). Similarly, DEHP(l00 mg/kg/day) was administered daily from postnatal day 25 through the day when the first V.O. in control group was observed, and the animals were sacrificed on the next day(day 36). To determine the transcriptional changes in the hormone receptors, total RNAs were extracted from ovary and uterus and were applied to semi-quantitative reverse transcription polymerase chain reaction(RT-PCR). In the GS group, the transcriptional activities of $ER\;{\alpha}$, $ER\;{\beta}$ and LHR in uterus and LHR in ovary were significantly increased when compared to those of control group. In the DEHP group, the transcriptional activities of all the hormone receptors measured were significantly lowered when compared to those of control group. These alteration of the reproductive hormone receptor expressions in ovary and uterus might be represent the phenotypic aspects(secondary sexual characteristics) such as tissue weights and reproductive hormone levels during perinatal period in immature female rats.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.18
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• pp.8135-8140
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• 2016

Background: Cell cycle regulatory proteins are suitable targets for cancer therapeutic development since genetic alterations in many cancers also affect the functions of these molecules. Strobilanthes crispus (S. crispus) is traditionally known for its potential benefits in treating various ailments. We recently reported that an active sub-fraction of S. crispus leaves (SCS) caused caspase-dependent apoptosis of human breast cancer MCF-7 and MDA-MB-231 cells. Materials and Methods: Considering the ability of SCS to also promote the activity of the antiestrogen, tamoxifen, we further examined the effect of SCS in modulating cell cycle progression and related proteins in MCF-7 and MDA-MB-231 cells alone and in combination with tamoxifen. Expression of cell cycle-related transcripts was analysed based on a previous microarray dataset. Results: SCS significantly caused G1 arrest of both types of cells, similar to tamoxifen and this was associated with modulation of cyclin D1, p21 and p53. In combination with tamoxifen, the anticancer effects involved downregulation of $ER{\alpha}$ protein in MCF-7 cells but appeared independent of an ER-mediated mechanism in MDA-MB-231 cells. Microarray data analysis confirmed the clinical relevance of the proteins studied. Conclusions: The current data suggest that SCS growth inhibitory effects are similar to that of the antiestrogen, tamoxifen, further supporting the previously demonstrated cytotoxic and apoptotic actions of both agents.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.10
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• pp.5105-5111
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• 2012

Background: Published data on the association between single nucleotide polymorphisms (SNPs) in the ESR1 gene and breast cancer susceptibility are inconclusive or controversial. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis was to derive a more precise estimation of this relationship. Methods: A literature search of Pubmed, Embase, Web of science and CBM databases was conducted from inception through September 1th, 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Results: A total of five studies including 1,678 breast cancer cases and 1,678 general population controls in Asian populations were involved in this meta-analysis. When all the eligible studies were pooled into the meta-analysis, the higher transcriptional activity variant allele T of ESR1 PvuII (C>T) (rs2234693) in pre-menopausal breast cancer women showed a significant relation to increased risk (OR = 1.13, 95%CI: 1.01-1.28, P = 0.040) in contrast to their post-menopausal counterparts which showed non-significant increased risk (OR = 1.01, 95%CI: 0.87-1.18, P = 0.858). Nevertheless, no significant association between ESR1 XbaI (A>G) (rs9340799) polymorphism and the risk of breast cancer was observed in pre-menopausal and post-menopausal individuals. Conclusion: Based on a homogeneous Asian population, results from the current meta-analysis indicates that the ESR1 PvuII (C>T) polymorphism places pre-menopausal breast cancer women at risk for breast cancer, while ESR1 XbaI (A>G) polymorphism is not likely to predict the risk of breast cancer.

• Journal of Breast Disease
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• v.6 no.2
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• pp.35-38
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• 2018

Purpose: The eighth American Joint Committee on Cancer staging system for breast cancer was recently published to more accurately predict the prognosis by adding biomarkers such as estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. However, this system is very complicated and difficult to use by clinicians. The authors developed a program to aid in setting up the staging system and confirmed its usefulness by applying it to theoretical combinations and actual clinical data. Methods: The program was developed using the Microsoft Excel Macro. It was used for the anatomic, clinical and pathological prognostic staging of 588 theoretical combinations. The stages were also calculated the stages using 840 patients with breast cancer without carcinoma in situ or distant metastasis who did not undergo preoperative chemotherapy. Results: The anatomic, clinical and pathological prognostic stages were identical in 240 out of 588 theoretical combinations. In the actual patients' data, stages IB and IIIB were more frequent in clinical and pathological prognostic stages than in the anatomic stage. The anatomic stage was similar to the clinical prognostic stage in 58.2% and to the pathological prognostic stage in 61.9% of patients. Oncotype DX changed the pathological prognostic stage in 2.1% of patients. Conclusion: We developed a program for the new American Joint Committee on Cancer staging system that will be useful for clinical prognostic prediction and large survival data analysis.

• Journal of Life Science
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• v.16 no.3 s.76
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• pp.546-554
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• 2006

To understand antitumor activity of Zanthoxylum schinfolium, which has been used as an aromatic and medicinal plant in Korea, the cytotoxic effect of various organic solvent extracts of its leaves on human tumor cells were investigated. Among these extracts such as methanol extract (SL-13), methylene chloride extract (SL-14), ethyl acetate extract (SL-15), n-butanol extract (SL-16), and residual fraction (SL-17), SL-14 appeared to contain the most cytotoxic activity against leukemia and breast cancer cells tested. The methylene chloride extra.1 (SL-14) possessed an apoptogenic activity causing apoptotic DNA fragmentation of human acute leukemia Jurkat T cells via mitochondrial cytochrome c release into cytoplasm, subsequent activation of caspase-9 and caspase-3, and cleavage of PARP, which could be negatively regulated by antiapoptotic protein Bcl-xL. The GC-MS analysis of SL-14 revealed that the twenty-two ingredients of SL-14 were 9,19-cyclolanost-24-en-3-ol (15.1%), 2-a-methyl-17, b-hop-21-ene (15.1%), 15-methyl-2,3-dihydro-1H benzazepin (11.95%), phytol (10.38%), lupeol (9.92%), 12-methylbenzofuran (8.23%), hexadecanoic acid (5.96%), cis,cis,cis-9,12,15-octadecatrienoic acid-methyl-ester (5.49%), 9,12,15-octadecatrienoic acid-methylester (3.59%), 15-methyl-4-(1-methylethylidene)-2-(4-nitrophenyl) (3.36%), hexadecanoic acid methyl ester (1.93%), vitamine E (1.88%), beta-amyrin (0.96%), and auraptene (0.89%). These results demonstrate that the cytotoxicity of the methylene chloride extract of the leaves of Z. schinifolium toward Jurkat T cells is mainly attributable to apoptosis mediated by mitochondria-dependent caspase cascade regulated by Bcl-xL, and provide an insight into the mechanism underlying antitumor activity of the edible plant Z. schinifolium.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.6135-6140
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• 2013

Background: Breast cancer is a common malignant tumor which affects health of women and multidrug resistance (MDR) is one of the main factors leading to failure of chemotherapy. This study was conducted to establish paclitaxel-resistant breast cancer cell line and nude mice models to explore underlying mechanisms of MDR. Methods: The breast cancer drug-sensitive cell line MCF-7 (MCF-7/S) was exposed in stepwise escalating paclitaxel (TAX) to induce a resistant cell line MCF-7/TAX. Cell sensitivity to drugs and growth curves were measured by MTT assay. Changes of cell morphology and ultrastructure were examined by optical and electron microscopy. The cell cycle distribution was determined by flow cytometry. Furthermore, expression of proteins related to breast cancer occurrence and MDR was tested by immunocytochemistry. In Vivo, nude mice were injected with MCF-7/S and MCF-7/TAX cells and weights and tumor sizes were observed after paclitaxel treatment. In addition, proteins involved breast cancer and MDR were detected by immunohistochemistry. Results: Compared to MCF-7/S, MCF-7/TAX cells had a higher resistance to paclitaxel, cross-resistance and prolonged doubling time. Moreover, MCF-7/TAX showed obvious alterations of ultrastructure. Estrogen receptor (ER) expression was low in drug resistant cells and tumors while expression of human epidermal growth factor receptor 2 (HER2) and Ki-67 was up-regulated. P-glycoprotein (P-gp), lung resistance-related protein (LRP) and glutathione-S-transferase-${\pi}$ (GST-${\pi}$) involved in the MDR phenotype of resistant cells and tumors were all overexpressed. Conclusion: The underlying MDR mechanism of breast cancer may involve increased expression of P-gp, LRP and GST-${\pi}$.

• The Korean Journal of Pharmacology
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• v.19 no.1
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• pp.37-60
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• 1983

The uterus receives adrenergic terminals from the mesenteric ganglia and considerably large amount of catecholamines have been shown to be contained in this organ. On the other hand, the activities of epinephrine, norepinephrine or adrenergic nerve on uterine motility is so complicated that many controversial results have been reporter. Recently, a large number of reports concerning the changes of uterine catecholamines content have appeared, but little is known about the role of uterine catecholamines in their activities on uterine motility. The present experiments were undertaken to determine the significance of the intrinsic uterine catecholamines in the physiology of uterus. Female albino rabbits weighing approximately 2 kg were employed in this experiment. uterine strip3 were prepared and suspended in a constant temperature $bath(38^{\circ}C)$ containing 100 ml of Locke's solution aerated with 95% oxygen and 5% carbon dioxide. Spontaneous motility was recorded on a smoked drum with an isotonic lever. The catecholamines concentration of the uterus was determined according to the Procedure described of Shore and Olin (1958). Human uterus obtained from patients was also used to determine the catecholam ines content of myometrium. Followings are summarized results. 1) On the non-pregnant rabbit uterine strips, epinephrine and norepinephrine significantly elevated the tonus and stimulated the spontaneous motility. Pretreatment with dichloroisoproterenol(DCI), an adrenergic beta-receptor blocker, enhanced the stimulatory activity of epinephrine or norepinephrine. On the other hand, pretreatment with dibenamine, an adrenergic alpha-receptor blocker, rendered the uterine muscle to exhibit inhibition after the administration of epinephrine or norepinephrine. Following the treatment with both DCI and dibenamine, epinephrine or norepinephrine produced no appreciable effects on the spontaneous motility of the uterus. These results suggest there exist both alpha and beta-adrenergic receptors in the uterine muscle and the response to epinephrine of the former is predominant over that of latter in the non-pregnant uterus of rabbits. The total catecholamines concentration of the non-pregnant uterus was $351\;m{\mu}g/g$ and the fractional concentrations of epinephrine and norepinephrine were $125\;m{\mu}g/g(35.7%)$ and $226\;m{\mu}g/g$ respectively. It is interesting to note that the catecholamines content of uterus was characterized by a high fractional corcentration of epinephrine relative to norepinephrine. 2) On the pregnant rabbit uterine strips, the effects of epinephrine and norepinephrine varied according to the period of pregnancy. The response to epinephrine of adrenergic beta receptor of uterus increased during pregnancy, and the effect of catecholamine was inhibitory in the early pregnancy but became stimulatory as the pregnancy progressed. This stimulating action on the uterine motility was found to occur through the action of norepinephrine. The uterine catecholamines concentration was markedly reduced during pregnancy. The catecholamines concentration was started to decrease in the early pregnancy, reached the lowest level in the mid-pregnancy and then started to increaae again in the late pregnancy when the total catecholamines content became the highest level of all. This increase of catefholamines in late pregnancy was chiefly due to the increase of norepinephrine. These results suggest that the uterine motility may be related to the catecholamines content, especially norepinephrine content in the uterus. 3) Bilateral oophorectomy of rabbits results in a marked shrink of the uterus in size. The spontaneous motility of the uterine segment of these animals was very weak and irregular. Norepinephrine produced inhibitory effect, whereas epinephrine was stimulatory or inhibitory effect on the uterine segment. The total catecholamines tontent in whole uterus was markedly reduced. The injection of estrogen into the oophorectornized rabbit increased the weight of uterus to approximately three times of that of oophorectornized animal. The apontaneous motility and the response to epinephrine and norepinephrine of the uterine segment were greatly enhanced. Both epinephrine and norepinephrine produced a marked stimulatory effects of the uterine motility. The uterine content of catecholamines, particularly epinephrine, was markedly increased. The injection of progesterone into the oophorectornized rabbit increaeed the weight of uterus to approximately 2.5 times of that of eophorectornized animal. The spontaneous motility of the uterine segment was weak and irregular. Epinephrine produced stimulatory effect at high concentrations but norepinephrine always prcdnced inhibitory effect on the uterine segment. The uterine content of catecholamines, particularly of norepinephrine, was markedly reduced. These results suggested that ovarian hormones play an important role not only on the growth and spontaneous norepinephrine of uterus but also on the catecholamines content and responee to epinephrine and norepinephrine of the uterus. 4) The intraperitoneal injection of reserpine(3 mg/kg) into the non-pregnant, pregnant and oophorectornieed rabbits markedly decreased the uterine content of catecholamines, particularly of the norepinephrine. The stimulatory response to epinephrine and. norepinephrine of the uterine segment of these reserpinized ratbits was markedly reduced whereas the inhibitory response to these catecholamines was enhanced. This finding further support the close relationship between the uterine catecholamines content and uterine response to epineptrire and norepinephrine. 5) In the human uterus, the concentration of epinephrine was actrally greater than that of norepinephrine and it was significantly greater during the proliferative phase of the menstrtal cycle. In the human pregnant uterus, the concentrations of toth epinephrine and ncrefinephrine were markedly reduced and showed about 45 percent rednction after 6-8 weeks of ectopic Pregnancy. At full term ana during labor, the concentrations of epinephrine and norepinephrine at placental sites were less than those found in the non-pregnant group. Of interest was the finding that the norepinephrine concentration of uterus from toxemic patients was two and half times higher than that of lower uterine segment of the nontoxemic pregnant individuals. Also the epinephrine concentraticn was slightly increaeed.