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resistance ( Wang et al . 2009 , Yang et al . 2010 ). In this study, we set out to investigate the therapeutic potential of FAK in the context of ER+/HER2+ breast cancer. Our initial observations revealed that there was no apparent correlation between
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, including STS and 17βHSD1 may also have important therapeutic potential as endocrine therapy for total blockade of local estrogen in breast cancer tissues. STS inhibitors were reported to be effective in suppressing the proliferation of estrogen
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Clinical Oncology Department, Department of Medical Oncology, University of Manchester, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Sorafenib is the only systemic therapy to demonstrate a significant survival benefit over supportive care in robust randomised controlled trials for advanced hepatocellular carcinoma (HCC). In the context of an intense search for prognostic and predictive factors for response and efficacy of different systemic therapies (including sorafenib), a number of molecular targets have been identified, paving new avenues for potential therapeutic opportunities. Such molecular targets include somatostatin receptor (SSTR)-related alterations. In this review, we provide an overview of the various considerations relating to SSTRs as potentially novel prognostic and predictive biomarkers for HCC with special emphasis on the therapeutic potential of somatostatin analogues in HCC management.
Consortium for the Study of Thyroid Cancer (CECaT), Catalonia, Spain
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Program of Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), Barcelona, Spain
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In recent years, cancer genomics has provided new insights into genetic alterations and signaling pathways involved in thyroid cancer. However, the picture of the molecular landscape is not yet complete. DNA methylation, the most widely studied epigenetic mechanism, is altered in thyroid cancer. Recent technological advances have allowed the identification of novel differentially methylated regions, methylation signatures and potential biomarkers. However, despite recent progress in cataloging methylation alterations in thyroid cancer, many questions remain unanswered. The aim of this review is to comprehensively examine the current knowledge on DNA methylation in thyroid cancer and discuss its potential clinical applications. After providing a general overview of DNA methylation and its dysregulation in cancer, we carefully describe the aberrant methylation changes in thyroid cancer and relate them to methylation patterns, global hypomethylation and gene-specific alterations. We hope this review helps to accelerate the use of the diagnostic, prognostic and therapeutic potential of DNA methylation for the benefit of thyroid cancer patients.
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Department of Internal Medicine, Department of Cell Biology, Simmons Cancer Center, Touchstone Diabetes Center
Department of Internal Medicine, Department of Cell Biology, Simmons Cancer Center, Touchstone Diabetes Center
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There is growing evidence that obesity is a risk factor of cancer incidence and mortality. Hence, the identification of the mechanistic links between obesity and cancer progression is emerging as a topic of widespread interest. Recently, several groups have addressed the functional roles of leptin, an adipocyte-derived adipokine, for mammary tumor progression. In this issue of Endocrine-Related Cancer, Zheng et al. study the role of leptin on tumor growth in a xenograft model of MMTV-Wnt1-derived cancer cells. They study growth of these cancer cells in the context of obese animals, such as ob/ob mice (lacking leptin) and db/db mice (lacking functional leptin receptors (LEPR)) and find that leptin triggers LEPR-positive cancer stem cell differentiation, thereby promoting tumor cell survival. These findings highlight the therapeutic potential for leptin and leptin signaling in the context of mammary tumor growth.
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The expression of estrogen receptor α (ERα) in breast cancer identifies patients most likely to respond to endocrine treatment. The second ER, ERβ, is also expressed in breast tumors, but its function and therapeutic potential need further study. Although in vitro studies have established that ERβ opposes transcriptional and proliferative functions of ERα, several clinical studies report its correlation with proliferative markers and poorer prognosis. The data demonstrate that ERβ opposes ERα are primarily based on transient expression of ERβ. Here, we explored the functions of constitutively expressed ERβ in ERα-positive breast cancer lines MCF7 and T47D. We found that ERβ, under these conditions heterodimerized with ERα in the presence and absence of 17β-estradiol, and induced genome-wide transcriptional changes. Widespread anti-ERα signaling was, however, not observed and ERβ was not antiproliferative. Tamoxifen antagonized proliferation and ER-mediated gene regulation both in the presence and absence of ERβ. In conclusion, ERβ‘s role in cells adapted to its expression appears to differ from its role in cells with transient expression. Our study is important because it provides a deeper understanding of ERβ's role in breast tumors that coexpress both receptors and supports an emerging bi-faceted role of ERβ.
Department of Reproductive Medicine Center, Key Laboratory for Reproductive Medicine of Guangdong Province, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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Sun Yat-sen University Cancer Center, Guangzhou, China
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Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
China Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China
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Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products (Sun Yat-sen University), Guangzhou, China
Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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Sorafenib, a small-molecule tyrosine kinase inhibitor with antiangiogenic activity, has been used in liver cancer and kidney cancer treatments. However, clinical trials with sorafenib for breast cancer were stopped in phase III due to limited efficacy. The existence of heterogeneous vasculatures involving tumor cells, such as vessel-like structures formed by vasculogenic mimicry and mosaic vessels, and their resistance to antiangiogenic therapy are thought to be a possible reason for failure of sorafenib therapy. Nevertheless, the features and mechanism of vasculogenesis by tumor cells remain unclear. In the present study, we found that breast cancer stem-like cells (BCSLCs, ALDH1+ cells) were involved in vasculogenic mimicry and mosaic vessel formation in triple-negative breast cancer tissues. Further, only ALDH1+ BCSLCs sorted from MDA-MB-231 could exhibit the tube formation and angiogenesis ability. Sorafenib could inhibit vascularization from endothelial cells rather than that from ALDH1+ cells. α-SMA was identified as a key molecule in vascular formation of BCSLCs. Mechanistically, HIF-1α enhanced the mRNA and protein levels of α-SMA by binding to the HRE element in the promoter directly and meanwhile increased the BCSLCs population. Interestingly, pigment epithelium-derived factor (PEDF), an endogenous angiogenesis inhibitor, could inhibit both endothelial cell-derived and tumor cell-derived angiogenesis by downregulating HIF-1α in breast cancer. Our finding clarified the possible reason for the poor outcome of anti-angiogenesis therapy and PEDF may have the therapeutic potential.
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Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
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Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy without effective therapeutic options to improve survival. Steroid receptor coactivator-3 (SRC-3) is a transcriptional coactivator whose amplification and/or overexpression has been identified in many cancers. In this study, we explored the expression of SRC-3 in ATCs and the effects of a new class of SRC-3 inhibitor-2 (SI-2) in human ATC cells (THJ-11T and THJ-16T cells) and mouse xenograft models to assess therapeutic potential of SI-2 for the treatment of ATC. SRC-3 protein abundance was significantly higher in human ATC tissue samples and ATC cells than in differentiated thyroid carcinomas or normal controls. SI-2 treatment effectively reduced the SRC-3 expression in both ATC cells and ATC xenograft tumors induced by these cells. Cancer cell survival in ATC cells and tumor growth in xenograft tumors were significantly reduced by SI-2 treatment through induction of cancer cell apoptosis and cell cycle arrest. SI-2 also reduced cancer stem-like cells as shown by an inhibition of tumorsphere formation, ALDH activity, and expression of stem cell markers in ATC. These findings indicate that SRC-3 is a potential therapeutic target for treatment of ATC patients and that SI-2 is a potent and promising candidate for a new therapeutic agent.
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Rac1, a Rho GTPase, modulates diverse cellular processes and is hyperactive in some cancers. Estrogen receptor-alpha (ERα) in concert with intracellular signaling pathways regulates genes associated with cell proliferation, tumor development, and breast cancer cell survival. Therefore, we examined the possibility of Rac1 and ERα crosstalk in breast cancer cells. We found that Rac1 enhanced ERα transcriptional activity in breast cancer cells. Vav3, a Rho guanine nucleotide exchange factor that activates Rac1, was an upstream mediator, and P21/Cdc42/Rac1 activating kinase-1 (Pak-1) was a downstream effector of Rac1 enhancement of ERα activity. These results suggest that Rac1 may prove to be a therapeutic target. To test this hypothesis, we used a small molecule Rac inhibitor, EHT 1864, and found that EHT 1864 inhibited ERα transcriptional activity. Furthermore, EHT 1864 inhibited estrogen-induced cell proliferation in breast cancer cells and decreased tamoxifen-resistant breast cancer cell growth. EHT 1864 decreased activity of the promoter of the ERα gene resulting in down-regulation of ERα mRNA and protein levels. Therefore, ERα down-regulation by EHT 1864 is the likely mechanism of EHT 1864-mediated inhibition of ERα activity and estrogen-stimulated breast cancer cell proliferation. Since ERα plays a critical role in the pathogenesis of breast cancer and the Rac inhibitor EHT 1864 down-regulates ERα expression and breast cancer cell proliferation, further investigation of the therapeutic potential of Rac1 targeting in the treatment of breast cancer is warranted.