• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.3857-3862
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• 2012

A total of 96 cases of invasive breast ductal carcinoma were examined for immunohistochemical expression of Bax and Bcl-2 in the epithelial tumor cells and endothelial cells of the blood vessels. We also investigated the association between both proteins in the epithelium in relation to tumor characteristics such as tumor size, grade, lymph node involvement, microvessel density (MVD), hormonal receptors expression and c-erbB-2 overexpression. Bax expression showed a significant association between tumor and endothelial cells (p<0.001) while Bcl-2 expression in tumor cells was inversely associated with that in the endothelial cells (p<0.001). Expression of Bcl-2 in tumor cells was strongly associated with expression of estrogen and progesterone receptors (p=0.003 and p=0.004, respectively). In addition, intratumoral MVD was significantly higher than peritumoral MVD (p<0.001) but not associated with Bax or Bcl-2 expression and other tumor characteristics. We concluded that the number of endothelial cells undergoing apoptosis was in direct linkage with the number of apoptotic tumor cells. Anti-apoptotic activity of the surviving tumor cells appears to propagate cancer progression and this was influenced by the hormonal status of the cells. Tumor angiogenesis was especially promoted in the intratumoral region and angiogenesis was independent of anti-apoptotic activity.

• Toxicological Research
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• v.27 no.4
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• pp.253-259
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• 2011

Transforming growth factor ${\beta}$ (TGF-${\beta}$) is involved in cellular processes including growth, differentiation, apoptosis, migration, and homeostasis. Generally, TGF-${\beta}$ is the inhibitor of cell cycle progression and plays a role in enhancing the antagonistic effects of many growth factors. Unlike the antiproliferative effect of TGF-${\beta}$, E2, an endogeneous estrogen, is stimulating cell proliferation in the estrogen-dependent organs, which are mediated via the estrogen receptors, $ER{\alpha}$ and $ER{\beta}$, and may be considered as a critical risk factor in tumorigenesis of hormone-responsive cancers. Previous researches reported the cross-talk between estrogen/$ER{\alpha}$ and TGF-${\beta}$ pathway. Especially, based on the E2-mediated inhibition of TGF-${\beta}$ signaling, we examined the inhibition effect of 4-tert-octylphenol (OP) and 4-nonylphenol (NP), which are well known xenoestrogens in endocrine disrupting chemicals (EDCs), on TGF-${\beta}$ signaling via semi-quantitative reverse-transcription PCR. The treatment of E2, OP, or NP resulted in the downregulation of TGF-${\beta}$ receptor2 (TGF-${\beta}$ R2) in TGF-${\beta}$ signaling pathway. However, the expression level of TGF-${\beta}1$ and TGF-${\beta}$ receptor1 (TGF-${\beta}$ R1) genes was not altered. On the other hand, E2, OP, or NP upregulated the expression of a cell-cycle regulating gene, c-myc, which is a oncogene and a downstream target gene of TGF-${\beta}$ signaling pathway. As a result of downregulation of TGF-${\beta}$ R2 and the upregulation of c-myc, E2, OP, or NP increased cell proliferation of BG-1 ovarian cancer cells. Taken together, these results suggest that E2 and these two EDCs may mediate cancer cell proliferation by inhibiting TGF-${\beta}$ signaling via the downregulation of TGF-${\beta}$ R2 and the upregulation of c-myc oncogene. In addition, it can be inferred that these EDCs have the possibility of tumorigenesis in estrogen-responsive organs by certainly representing estrogenic effect in inhibiting TGF-${\beta}$ signaling.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.6
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• pp.2935-2940
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• 2016

Breast cancer is the most frequent type of cancer diagnosed among women worldwide and also in Thailand. Estrogen and estrogen receptors exert important roles in its genesis and progression. Several cytokines have been reported to be involved in the microenvironment that promotes distant metastasis via modulation of immune and inflammatory responses to tumor cells. Estrogen receptor genetic polymorphisms and several cytokines have been reported to be associated with breast cancer susceptibility and aggressiveness. To investigate roles of genetic polymorphisms in estrogen receptor alpha (ESR1) and interleukin 6 (IL6), breast cancer patients and control subjects were recruited from the Division of Head, Neck and Breast Surgery (Siriraj Hospital, Bangkok, Thailand). Polymorphisms in ESR1 (rs3798577) and IL6 (rs1800795 and rs1800797) were evaluated by real-time PCR in 391 breast cancer patients and 79 healthy controls. Associations between genetic polymorphisms and clinicopathological data were determined. There was no association between genetic polymorphisms and breast cancer susceptibility. However the ESR1 rs3798577 CT genotype was associated with presence of lymphovascular invasion (OR=2.07, 95%CI 1.20-3.56, p=0.009) when compared to the TT genotype. IL6 rs1800795 CC genotype was associated with presence of extranodal extension (OR= 2.30, 95%CI 1.23-4.31, p=0.009) when compared to the GG genotype. Survival analysis showed that IL6 rs1800797 AG or AA genotypes were associated with lower disease-free survival. These findings indicate that polymorphisms in ESR1 and IL6 contribute to aggressiveness of breast cancer and may be used to identify high risk patients.

• Biomolecules & Therapeutics
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• v.16 no.3
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• pp.293-298
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• 2008

Cirsium japonicum water extracts has been used to treat vascular related diseases. We have previously reported that Cirsium japonicum extracts activated estrogen receptors. It is widely known that estrogen increases the high density lipoprotein cholesterol and decrease the low density lipoprotein cholesterol on the lipid profile. But effects of Cirsium japonicum on lipid profile are not reported yet. Therefore, we have studied the effects of Cirsium japonicum on the lipid content in ovariectomized rats. Thirty Sprague-Dawley (SD) rats of $210{\pm}20\;g$ were studied for 10 weeks. The rats were divided into five groups; (I) sham, no ovariectomized rats plus olive oil, (II) ovariectomized rats plus olive oil, (III) ovariectomized rats plus 0.5 mg/kg $17{\beta}$-estradiol (E2) in olive oil, (IV) ovariectomized rats plus 0.5 mg/kg Cirsium japonicum in olive oil, and (V) ovariectomized rats plus 5 mg/kg Cirsium japonicum in olive oil. Treatment with Cirsium japonicum or E2 induced significant reduction in total cholesterol, low density lipoprotein cholesterol/total cholesterol, total cholesterol/high density lipoprotein cholesterol and low density lipoprotein cholesterol/high density lipoprotein cholesterol compared to control group as well as increase in uterine weight. However, changes in triglycerides levels were different. Our results suggest that Cirsium japonicum is functionally similar to E2 in vivo as well as in vitro.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1507-1512
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• 2016

Background: Risk of developing breast cancer increases with short breastfeeding and the use of hormones. The prognosis of breast cancer is better if the tumours are hormone receptor positive. Since breast feeding affects estrogen and progesterone receptors, we wanted to investigate how such reproductive factors as breastfeeding and the use of hormones interact with known prognostic markers and specific tumour characteristics in women with breast cancer. Materials and Methods: A total of 250 women treated for breast cancer from a larger cohort completed a questionnaire on breastfeeding, number and age at births and use of hormones. A logistic regression analysis was made to search for connections between known prognostic markers on the one hand (type of cancer, grade, tumor size, estrogen receptor and progesterone receptor, lymphovascular invasion and DNA-ploidy) and reproductive data, breastfeeding, and hormone use on the other. Results and Conclusions: Hormone use, but not breastfeeding, was significantly associated, also on multivariate analysis, with the prognostic variable lymphovascular invasion, connected to a worse prognosis. No other hormone use or breast feeding correlations with prognostic variables were found.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.7
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• pp.3035-3041
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• 2016

Breast cancer (BC) is the most common malignancy of women worldwide. In the past it was considered as disease of older middle aged women, but the incidence of BC in young females is growing in recent years concordant with studies in Pakistan. In this paper, we reviewed the mutant functions of tumor suppressor genes (BRCA1, BRCA2, p53, ATM and PTEN), epigenetic transformation and involvement of estrogen receptors in development of breast cancer. We further reviewed the current situation of BC in Pakistan that depicts a higher incidence in young females. According to SKMCH and RC data, age group 45-49 years is more prone to BC with high rate of incidence 45.42%. A few studies explored the high expression of ER, PR and HER-2/neu in Pakistani females. Moreover, presence of BRCA1 (c.1961dupA) mutation in Pakistani shows concordance with data in different areas of world. But we are unable to find an authentic study that can explore epigenetic based transformation of breast tumors in Pakistan. This area of research needs more attention to explore the complete picture of BC in Pakistan.

• Proceedings of the Korean Society of Developmental Biology Conference
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• 2001.02a
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• pp.50-51
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• 2001

In ultrastructure study of testis, Sertoli cells start to differentiate at 16 days of gestation. Transcripts of FSH receptor, IGF-I receptor, ER $\alphareceptor, $ $TGF-\beta$ receptor and androgen receptor were highly and initially expressed at 16 day of gestation. As results of in situ PCR at 16 day of gestation, transcripts of FSH, IGF-I receptor were detected in Sertoli cells and spermatogonia, whereas the receptors of $ER\alpha, $ $TGF-\beta$ and androgen were detected in Sertoli cells. Therefore, expression of FSH and estrogen $\alpha, $ androgen, IGF-I and $TGF-\alpha$ could play an important role during fetal and prepubertal testicular development by stage specific manner in mouse.

• BMB Reports
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• v.48 no.6
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• pp.342-347
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• 2015

The expression of epidermal growth factor receptor (EGFR) is an important diagnostic marker for triple-negative breast cancer (TNBC) cells, which lack three hormonal receptors: estrogen and progesterone receptors as well as epidermal growth factor receptor 2. EGFR transactivation can cause drug resistance in many cancers including TNBC, but the mechanism underlying this phenomenon is poorly defined. Here, we demonstrate that insulin treatment induces EGFR activation by stimulating the interaction of EGFR with insulin-like growth factor receptor 1 (IGF-1R) in the MDA-MB-436 TNBC cell line. These cells express low levels of EGFR, while exhibiting high levels of IGF-1R expression and phosphorylation. Low-EGFRexpressing MDA-MB-436 cells show high sensitivity to insulinstimulated cell growth. Therefore, unexpectedly, insulin stimulation induced EGFR transactivation by regulating its interaction with IGF-1R in low-EGFR-expressing TNBC cells. [BMB Reports 2015; 48(6): 342-347]

• Molecular & Cellular Toxicology
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• v.1 no.1
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• pp.52-61
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• 2005

Transcript profiling is a particularly valuable tool in the field of steroid receptor biology, as these receptors are ligand-activated transcription factors and therefore exert their initial effects through altering gene expression in responsive cells. Also, an awareness of endocrine disrupting chemicals (EDCs) and their potential screening methods to identify endocrine activity have been increased. Here we developed an in-house cDNA microarray, named KISTCHIP-400 ver. 1.0, with 416 clones, based on public database and research papers. These clones contained estrogen, androgen, thyroid hormone & receptors, sex hormone signal transduction & regulation, c-fos, c-myc, ps2 gene, metabolism related genes etc. Also, to validate the KISTCHIP-400 ver. 1.0, we investigated gene expression profiles with reference hormones, $10^{8}\;M\;17{\beta}-estradiol,\;10^{-7}\;M\;testosterone\;and\;10^{-7}\;M$ progesterone in MCF-7 cell line. As the results, gene expression profiles of three reference hormones were distinguished from each other with significant and identified 33 $17{\beta}-estradiol$ responsive genes. This study is in first step of validation for KISTCHIP-400 ver. 1.0, as following step transcriptional profile analysis on not only low concentrations of EDCs but suspected EDCs using KISTCHIP-400 ver. 1.0 is processing. Our results indicate that the developed microarray may be a useful laboratory tool for screening EDCs and elucidating endocrine disrupting mechanism.

• Proceedings of the Korea Society of Environmental Toocicology Conference
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• 2003.05a
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• pp.180-180
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• 2003

Transcript profiling is a particularly valuable tool in the field of steroid receptor biology, as these receptors are ligand-activated transcription factors and therefore exert their initial effects through altering gene expression in responsive cells. Also, an increased awareness of endocrine disrupting chemicals (EBCs) and their potential to affect wildlife and humans has produced a demand for practical screening methods to identify endocrine activity. Here we developed an in-house cDNA microarray, named KISTCHIP-400, with 401 clones, hormone related genes, factors, and ESTs, based on public database and research papers. Theses clones contained estrogen, androgen, thyroid hormone St receptors, sex hormone signal transduction ＆ regulation, c-fos, c-myc, ps2 gene, metabolism related genes etc. And to validate the KISTCHIP-400, we investigated gene expression profiles with reference hormones, 10$\^$-8/ M 17be1a-estradiol, 10$\^$-7/ M testosterone, 10$\^$-7/ M progesterone, and thyroxin in MCF-7 cell line. Although it is in first step of validation, low doses and combinations of EDCs need to be tested. Our preliminary results that indicate the developed microarray may be a useful laboratory tool for screening EDCs and elucidating endocrine disrupting mechanism.