Pub Date : 2011-01-01DOI: 10.2174/1874079001104010001
Jessica Diann Hathaway, Azizul Haque
Melanoma is the deadliest form of skin cancer in the United States with an increasing prevalence. However, the development of melanoma from a melanocyte precursor is still poorly defined. Understanding the molecules responsible for melanoma progression may lead to improved targeted therapy. One potential molecule is the paired box-3 (PAX-3) protein, which has been implicated in the development of melanocytes and malignant melanoma. In melanoma, the expression of PAX-3 is believed to be differentially regulated, and has been linked with malignancies and staging of the disease. The loss of PAX-3 regulation has also been associated with the loss of transforming growth factor-beta (TGF-β) activity, but its effect on PAX-3 in differentiated melanocytes as well as metastatic melanoma remains unclear. Understanding PAX-3 regulation could potentially shift melanoma to a less aggressive and less metastatic disease. This review summarizes our current knowledge on PAX-3 during melanocyte development, its regulation, and its implications in the development of novel chemo-immunotherapeutics against metastatic melanoma.
{"title":"Insights into the Role of PAX-3 in the Development of Melanocytes and Melanoma.","authors":"Jessica Diann Hathaway, Azizul Haque","doi":"10.2174/1874079001104010001","DOIUrl":"https://doi.org/10.2174/1874079001104010001","url":null,"abstract":"<p><p>Melanoma is the deadliest form of skin cancer in the United States with an increasing prevalence. However, the development of melanoma from a melanocyte precursor is still poorly defined. Understanding the molecules responsible for melanoma progression may lead to improved targeted therapy. One potential molecule is the paired box-3 (PAX-3) protein, which has been implicated in the development of melanocytes and malignant melanoma. In melanoma, the expression of PAX-3 is believed to be differentially regulated, and has been linked with malignancies and staging of the disease. The loss of PAX-3 regulation has also been associated with the loss of transforming growth factor-beta (TGF-β) activity, but its effect on PAX-3 in differentiated melanocytes as well as metastatic melanoma remains unclear. Understanding PAX-3 regulation could potentially shift melanoma to a less aggressive and less metastatic disease. This review summarizes our current knowledge on PAX-3 during melanocyte development, its regulation, and its implications in the development of novel chemo-immunotherapeutics against metastatic melanoma.</p>","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"4 ","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002046/pdf/nihms434197.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32309712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2010-09-23DOI: 10.2174/1874079001003010049
Fu Li, J. Wallace, Michael C. Ostrowski
ETS factors are involved in cancer progression through transcriptional regulation of factors mediating cell cycle, cell growth, apoptosis, cell adhesion and migration. The biological processes regulated by ETS factors are important not only in tumor cells, but also in the surrounding cells comprising the tumor microenvironment. Additionally, ETS factors can serve as transcriptional activators and repressors to regulate gene expression in a cell context-specific fashion. Here we discuss recent advances in which the regulatory roles of ETS factors in stromal cells are critical during both development and cancer. These new findings uncover the importance of ETS signaling in the stromal compartment of tumors and shed light on new potential mechanisms of ETS factors.
{"title":"ETS Transcription Factors in the Tumor Microenvironment","authors":"Fu Li, J. Wallace, Michael C. Ostrowski","doi":"10.2174/1874079001003010049","DOIUrl":"https://doi.org/10.2174/1874079001003010049","url":null,"abstract":"ETS factors are involved in cancer progression through transcriptional regulation of factors mediating cell cycle, cell growth, apoptosis, cell adhesion and migration. The biological processes regulated by ETS factors are important not only in tumor cells, but also in the surrounding cells comprising the tumor microenvironment. Additionally, ETS factors can serve as transcriptional activators and repressors to regulate gene expression in a cell context-specific fashion. Here we discuss recent advances in which the regulatory roles of ETS factors in stromal cells are critical during both development and cancer. These new findings uncover the importance of ETS signaling in the stromal compartment of tumors and shed light on new potential mechanisms of ETS factors.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"15 1","pages":"49-54"},"PeriodicalIF":0.0,"publicationDate":"2010-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68050883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2010-09-23DOI: 10.2174/1874079001003010040
David P Turner
Most advanced prostate tumors are dependent upon hormonal regulation of the transcriptional activity of the androgen receptor (AR). Current ASCO recommendations for initial treatment of advanced disease target the hormonal mediated regulation of AR activation through androgen deprivation therapy. Despite early treatment efficacy, most prostate tumors progress and re-activate AR transcriptional regulation through alternative biological mechanisms that allow them to circumvent the requirement for androgen. It is the temporal and spatial recruitment of specific AR transcriptional complexes to the promoters of cancer associated target genes that promotes the tumorigenic phenotype in prostate cancer. Increasing published data associates the E Twenty Six (ETS) family of transcription factors with prostate cancer progression and with the transcriptional activity of the AR. Evidence suggests that ETS factors act in concert to both positively and negatively regulate the pathways that control progression to metastatic cancer in prostate tissues. Given the critical roles both ETS factors and the AR play in the development of prostate cancer, mechanistic insight into their transcriptional co-regulation during the hormone sensitive and hormone refractory phases of progression will be provided by determining the contribution of ETS, AR and ETS-AR mediated regulatory control. This review examines the current depth of understanding of the role of the ETS family of transcription factors as transcriptional elements that confer the carcinogenic response to aberrant hormonal activity during prostate cancer progression.
{"title":"The Role of ETS Transcriptional Regulation in Hormone Sensitive and Refractory Prostate Cancer","authors":"David P Turner","doi":"10.2174/1874079001003010040","DOIUrl":"https://doi.org/10.2174/1874079001003010040","url":null,"abstract":"Most advanced prostate tumors are dependent upon hormonal regulation of the transcriptional activity of the androgen receptor (AR). Current ASCO recommendations for initial treatment of advanced disease target the hormonal mediated regulation of AR activation through androgen deprivation therapy. Despite early treatment efficacy, most prostate tumors progress and re-activate AR transcriptional regulation through alternative biological mechanisms that allow them to circumvent the requirement for androgen. It is the temporal and spatial recruitment of specific AR transcriptional complexes to the promoters of cancer associated target genes that promotes the tumorigenic phenotype in prostate cancer. Increasing published data associates the E Twenty Six (ETS) family of transcription factors with prostate cancer progression and with the transcriptional activity of the AR. Evidence suggests that ETS factors act in concert to both positively and negatively regulate the pathways that control progression to metastatic cancer in prostate tissues. Given the critical roles both ETS factors and the AR play in the development of prostate cancer, mechanistic insight into their transcriptional co-regulation during the hormone sensitive and hormone refractory phases of progression will be provided by determining the contribution of ETS, AR and ETS-AR mediated regulatory control. This review examines the current depth of understanding of the role of the ETS family of transcription factors as transcriptional elements that confer the carcinogenic response to aberrant hormonal activity during prostate cancer progression.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"3 1","pages":"40-48"},"PeriodicalIF":0.0,"publicationDate":"2010-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68050851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2010-09-23DOI: 10.2174/1874079001003010024
D. Watson, David P Turner, Melissa N. Scheiber, V. Findlay, P. Watson
ETS factors are known to act as positive or negative regulators of the expression of genes including those that control response to various signaling cascades, cellular proliferation, differentiation, hematopoiesis, apoptosis, adhesion, migration, invasion and metastasis, tissue remodeling, ECM composition and angiogenesis. During cancer progression, altered ETS gene expression disrupts the regulated control of many of these biological processes. Although it was originally observed that specific ETS factors function either as positive or negative regulators of transcription, it is now evident that the same ETS factor may function in reciprocal fashions, reflecting promoter and cell context specificities. This report will present a discussion of ETS factor expression during prostate and breast cancer progression and its functional roles in epithelial cell phenotypes. The ETS genes encode transcription factors that have independent activities but are likely to be part of an integrated network. While previous studies have focused on single ETS factors in the context of specific promoters, future studies should consider the functional impact of multiple ETS present within a specific cell type. The pattern of ETS expression within a single tissue is, not surprisingly, quite complex. Multiple ETS factors may be able to regulate the same genes, albeit at different magnitude or in different directions. Furthermore, the precise balance between cancer promotion and inhibition by ETS factors, which may differentially regulate specific target genes, can thus control its progression. These concepts form the basis of the hypothesis that "Ets conversion" plays a critical role during tumor progression. Examples supporting this hypothesis will be described.
{"title":"ETS Transcription Factor Expression and Conversion During Prostate and Breast Cancer Progression","authors":"D. Watson, David P Turner, Melissa N. Scheiber, V. Findlay, P. Watson","doi":"10.2174/1874079001003010024","DOIUrl":"https://doi.org/10.2174/1874079001003010024","url":null,"abstract":"ETS factors are known to act as positive or negative regulators of the expression of genes including those that control response to various signaling cascades, cellular proliferation, differentiation, hematopoiesis, apoptosis, adhesion, migration, invasion and metastasis, tissue remodeling, ECM composition and angiogenesis. During cancer progression, altered ETS gene expression disrupts the regulated control of many of these biological processes. Although it was originally observed that specific ETS factors function either as positive or negative regulators of transcription, it is now evident that the same ETS factor may function in reciprocal fashions, reflecting promoter and cell context specificities. This report will present a discussion of ETS factor expression during prostate and breast cancer progression and its functional roles in epithelial cell phenotypes. The ETS genes encode transcription factors that have independent activities but are likely to be part of an integrated network. While previous studies have focused on single ETS factors in the context of specific promoters, future studies should consider the functional impact of multiple ETS present within a specific cell type. The pattern of ETS expression within a single tissue is, not surprisingly, quite complex. Multiple ETS factors may be able to regulate the same genes, albeit at different magnitude or in different directions. Furthermore, the precise balance between cancer promotion and inhibition by ETS factors, which may differentially regulate specific target genes, can thus control its progression. These concepts form the basis of the hypothesis that \"Ets conversion\" plays a critical role during tumor progression. Examples supporting this hypothesis will be described.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"3 1","pages":"24-39"},"PeriodicalIF":0.0,"publicationDate":"2010-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68050829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2010-09-23DOI: 10.2174/1874079001003010022
D. Watson
The special issue provides a compilation of five review articles and five research articles on ETS transcriptional control, microRNA regulation of mRNA degradation and translation, post-transcriptional control of pre-RNA processing, protein stability and degradation. Thus, this issue highlights the areas that represent the main control mechanisms of gene expression from primary transcription to protein expression.
{"title":"Editorial-Transcriptional and Post-Transcriptional Regulation in Hormone-Dependent Cancer","authors":"D. Watson","doi":"10.2174/1874079001003010022","DOIUrl":"https://doi.org/10.2174/1874079001003010022","url":null,"abstract":"The special issue provides a compilation of five review articles and five research articles on ETS transcriptional control, microRNA regulation of mRNA degradation and translation, post-transcriptional control of pre-RNA processing, protein stability and degradation. Thus, this issue highlights the areas that represent the main control mechanisms of gene expression from primary transcription to protein expression.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"21 1","pages":"22-23"},"PeriodicalIF":0.0,"publicationDate":"2010-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68050771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2010-08-27DOI: 10.2174/1874079001003010016
Zarrag Isa Al-Fify, M. Aly
Cancer is a major cause of death in the world; thus, the prevention of this disease would have a significant impact on public health. Chemoprevention is defined as natural and synthetic pharmacological (chemical) agent to disrupt the process of carcinogenesis. Green tea is a potent chemopreventive agent in many test systems and has been shown to inhibit tumor promotion and induce apoptosis. It is one of the most frequently consumed beverages in the world. Green tea polyphenolics have demonstrated antimutagenic, anticarcinogenic, antioxidant and antipromotional effects. The aim of this work is to study the protective effect of green tea extract against genotoxic damage of dimethylnitros- amine (DMN) in mice bone marrow cells. Our results demonstrated that the administration of green tea extract 24 hr before the DMN injection significantly suppressed DMN-induced chromosomal aberrations and sister chromatid exchanges. The suppression was observed 18 hr, 24 hr and 48 hr after the DMN treatment but no suppressive effect was observed at the early period (6 hr and 12 hr) after the DMN treatment. Furthermore, the suppression was observed in all doses of DMN (4, 5 and 6 mg/kg) investigated. Mice were given green tea 2 hr before the DMN injection displayed no suppressive effect. Mice were given 2% green tea extract as the sole source of drinking water for four days before sacrifice displayed significantly suppressed DMN-induced chromosomal aberrations and sister chromatid exchanges. We conclude that green tea presents significant antigenotoxic concern under the anticipated conditions of use. These results are consistent with other antigenotoxicity studies of green tea.
{"title":"Protective Effect of Green Tea Against Dimethylnitrosamine Induced Genotoxicity in Mice Bone Marrow Cells","authors":"Zarrag Isa Al-Fify, M. Aly","doi":"10.2174/1874079001003010016","DOIUrl":"https://doi.org/10.2174/1874079001003010016","url":null,"abstract":"Cancer is a major cause of death in the world; thus, the prevention of this disease would have a significant impact on public health. Chemoprevention is defined as natural and synthetic pharmacological (chemical) agent to disrupt the process of carcinogenesis. Green tea is a potent chemopreventive agent in many test systems and has been shown to inhibit tumor promotion and induce apoptosis. It is one of the most frequently consumed beverages in the world. Green tea polyphenolics have demonstrated antimutagenic, anticarcinogenic, antioxidant and antipromotional effects. The aim of this work is to study the protective effect of green tea extract against genotoxic damage of dimethylnitros- amine (DMN) in mice bone marrow cells. Our results demonstrated that the administration of green tea extract 24 hr before the DMN injection significantly suppressed DMN-induced chromosomal aberrations and sister chromatid exchanges. The suppression was observed 18 hr, 24 hr and 48 hr after the DMN treatment but no suppressive effect was observed at the early period (6 hr and 12 hr) after the DMN treatment. Furthermore, the suppression was observed in all doses of DMN (4, 5 and 6 mg/kg) investigated. Mice were given green tea 2 hr before the DMN injection displayed no suppressive effect. Mice were given 2% green tea extract as the sole source of drinking water for four days before sacrifice displayed significantly suppressed DMN-induced chromosomal aberrations and sister chromatid exchanges. We conclude that green tea presents significant antigenotoxic concern under the anticipated conditions of use. These results are consistent with other antigenotoxicity studies of green tea.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68050746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2010-05-05DOI: 10.2174/1874079001003010001
J. Shukla, V. S. Thakur, T. Poduval
The electrostatic attraction between the negatively charged components of cancer cells and the positively charged anticancer peptides (ACPs) is believed to play a role in selective disruption of cancer cell membrane. Since arginine (Arg), a cationic amino acid is the most prevalent in these ACPs; we hypothesized that Arg when delivered in saline environment at the pharmacological concentration could become an anticancer molecule. The effects of L-Arg and D-Arg on tumor cell lines were studied. The therapeutic ability of pharmacological doses of Arg in saving the mice from experimental tumors was also evaluated. Both the enantiomers of Arg and not the cationic amino acid L-lysine (L-Lys) or agmatine-sulphate, at 10 mM concentration caused tumor cell clumping when treated in PBS. Arg delivered in PBS (Arg- P) and not in medium (Arg-M) up to 50 mM caused extensive tumor cell membrane damage leading to its death. Arg at 150 mM and above irrespective of chirality and incubation vehicle became an effective antitumor molecule against all the four cell lines tested. L-Arg was not toxic to normal cells like erythrocytes, lymphocytes, NIH 3T3 cells when presented in PBS. Arg cured mice bearing solid tumor fibrosarcoma (FS) when delivered into the tumor either in PBS or medium and lymphosarcoma-ascitic (LSA) tumor when delivered intraperitoneally in PBS. Our studies indicate that Arg can be used for loco-regional tumor therapy with minimal damage to normal cells and the mechanism of anticancer action of Arg is not metabolically driven but through its chemical structure, dose and delivery environment.
{"title":"Arginine: Appropriate Dose and Delivery Environment Makes It an Anticancer Molecule","authors":"J. Shukla, V. S. Thakur, T. Poduval","doi":"10.2174/1874079001003010001","DOIUrl":"https://doi.org/10.2174/1874079001003010001","url":null,"abstract":"The electrostatic attraction between the negatively charged components of cancer cells and the positively charged anticancer peptides (ACPs) is believed to play a role in selective disruption of cancer cell membrane. Since arginine (Arg), a cationic amino acid is the most prevalent in these ACPs; we hypothesized that Arg when delivered in saline environment at the pharmacological concentration could become an anticancer molecule. The effects of L-Arg and D-Arg on tumor cell lines were studied. The therapeutic ability of pharmacological doses of Arg in saving the mice from experimental tumors was also evaluated. Both the enantiomers of Arg and not the cationic amino acid L-lysine (L-Lys) or agmatine-sulphate, at 10 mM concentration caused tumor cell clumping when treated in PBS. Arg delivered in PBS (Arg- P) and not in medium (Arg-M) up to 50 mM caused extensive tumor cell membrane damage leading to its death. Arg at 150 mM and above irrespective of chirality and incubation vehicle became an effective antitumor molecule against all the four cell lines tested. L-Arg was not toxic to normal cells like erythrocytes, lymphocytes, NIH 3T3 cells when presented in PBS. Arg cured mice bearing solid tumor fibrosarcoma (FS) when delivered into the tumor either in PBS or medium and lymphosarcoma-ascitic (LSA) tumor when delivered intraperitoneally in PBS. Our studies indicate that Arg can be used for loco-regional tumor therapy with minimal damage to normal cells and the mechanism of anticancer action of Arg is not metabolically driven but through its chemical structure, dose and delivery environment.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68050702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2010-01-01DOI: 10.2174/1874079001003010116
Angelika M Burger, Fathima Kona, Yutaka Amemiya, Yuguang Gao, Stephanie Bacopulos, Arun K Seth
The BCA2 protein contains a RING H2 finger and a Zn finger near the N-terminus and has E3 ligase activity. RING finger proteins play critical roles in mediating the transfer of ubiquitin and ubiquitin like modifiers to heterologous substrates as well as to the RING finger proteins themselves. Protein modification by ubiquitin and small ubiquitin-related modifier (SUMO) plays a pivotal role in protein homeostasis and is critical to regulating basic cellular processes such as proliferation, differentiation, apoptosis, intracellular signaling, and gene-transcriptional regulation. The addition of ubiquitin or SUMO can modulate the ability of proteins to interact with their partners, alter their patterns of sub-cellular localization and control their stability. It is clear that SUMO influences many different biological processes however recent data suggest that it is specifically important in the regulation of transcription. BCA2 is an E3 ligase that interacts with the SUMO conjugating enzyme Ubc9. It could therefore function as an E3 in the sumoylation of various transcription factors. We have found that the BCA2 is co-expressed with the estrogen receptor in 74% of ER-positive invasive ductal carcinomas from a 635 member breast cancer cohort (p = 0.004). At the cellular level, BCA2 co-localizes with ER and it appears that at the transcriptional level BCA2 mRNA expression is regulated by estrogen. Bioinformatic analysis of the BCA2 promoter region revealed ER and PR binding sites as well as that of other more general transcription factors. The data presented here provides an overview of the potential involvement of the BCA2 in hormone responsive breast cancer and opens up avenues that should be exploited to better understand the regulation of ER expression, growth of breast cancer cells, and the importance of BCA2.
{"title":"Role of the BCA2 ubiquitin E3 ligase in hormone responsive breast cancer.","authors":"Angelika M Burger, Fathima Kona, Yutaka Amemiya, Yuguang Gao, Stephanie Bacopulos, Arun K Seth","doi":"10.2174/1874079001003010116","DOIUrl":"10.2174/1874079001003010116","url":null,"abstract":"<p><p>The BCA2 protein contains a RING H2 finger and a Zn finger near the N-terminus and has E3 ligase activity. RING finger proteins play critical roles in mediating the transfer of ubiquitin and ubiquitin like modifiers to heterologous substrates as well as to the RING finger proteins themselves. Protein modification by ubiquitin and small ubiquitin-related modifier (SUMO) plays a pivotal role in protein homeostasis and is critical to regulating basic cellular processes such as proliferation, differentiation, apoptosis, intracellular signaling, and gene-transcriptional regulation. The addition of ubiquitin or SUMO can modulate the ability of proteins to interact with their partners, alter their patterns of sub-cellular localization and control their stability. It is clear that SUMO influences many different biological processes however recent data suggest that it is specifically important in the regulation of transcription. BCA2 is an E3 ligase that interacts with the SUMO conjugating enzyme Ubc9. It could therefore function as an E3 in the sumoylation of various transcription factors. We have found that the BCA2 is co-expressed with the estrogen receptor in 74% of ER-positive invasive ductal carcinomas from a 635 member breast cancer cohort (p = 0.004). At the cellular level, BCA2 co-localizes with ER and it appears that at the transcriptional level BCA2 mRNA expression is regulated by estrogen. Bioinformatic analysis of the BCA2 promoter region revealed ER and PR binding sites as well as that of other more general transcription factors. The data presented here provides an overview of the potential involvement of the BCA2 in hormone responsive breast cancer and opens up avenues that should be exploited to better understand the regulation of ER expression, growth of breast cancer cells, and the importance of BCA2.</p>","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"3 1","pages":"116-123"},"PeriodicalIF":0.0,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004234/pdf/nihms186583.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29553501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-12-19DOI: 10.2174/1874079000802010059
J. Baranowska-Kortylewicz, Jessica Nearman, Z. Kortylewicz
Sex hormone-binding globulin (SHBG) is the major carrier protein of testosterone and estradiol in the blood. Although studies on the role of SHBG in ovarian cancer are inconclusive, substantial evidence indicates that SHBG- steroid complexes can play a direct role in the intracellular transport of steroids to cancer cells. SHBG is synthesized in the adult liver of many species, excluding rodents. Adult mouse and rat livers do not produce SHBG, and yet most experimental models of ovarian cancer employ these species. Data reported here indicate that SHBG has a major stimulatory effect on the growth of human ovarian cancer in athymic mice. The effect is observed in subcutaneous and intraperitoneal OVCAR-3 xenografts. Tumor doubling times were 9.98±0.14 days and 17.20±0.64 days when OVCAR-3 cells were implanted with and without SHBG, respectively (P = 0.023). The magnitude of SHBG effect depended on the age of mice and it was most prominent in the development of intraperitoneal solid tumor deposits. Levels of circulating CA-125 were also age- and tumor size-dependent. Biodistribution studies of 125 I-SHBG indicated a prolonged retention of the protein in solid tumor deposits. Estimated half-lives of 125 I-SHBG were 2.3� longer in solid tumors as compared to nonadherent cancer cells in the peritoneal lavage. The normal tissue distribution of 125 I-SHBG was similar in control and OVCAR-3-bearing mice. These data suggest that currently used models of ovarian cancer in mice, including carcinogenesis and drug evaluation studies, are imperfect because of the lack of SHBG production in these species.
{"title":"Effect of Sex Hormone Binding Globulin on the Development of Ovarian Cancer in a Mouse Model","authors":"J. Baranowska-Kortylewicz, Jessica Nearman, Z. Kortylewicz","doi":"10.2174/1874079000802010059","DOIUrl":"https://doi.org/10.2174/1874079000802010059","url":null,"abstract":"Sex hormone-binding globulin (SHBG) is the major carrier protein of testosterone and estradiol in the blood. Although studies on the role of SHBG in ovarian cancer are inconclusive, substantial evidence indicates that SHBG- steroid complexes can play a direct role in the intracellular transport of steroids to cancer cells. SHBG is synthesized in the adult liver of many species, excluding rodents. Adult mouse and rat livers do not produce SHBG, and yet most experimental models of ovarian cancer employ these species. Data reported here indicate that SHBG has a major stimulatory effect on the growth of human ovarian cancer in athymic mice. The effect is observed in subcutaneous and intraperitoneal OVCAR-3 xenografts. Tumor doubling times were 9.98±0.14 days and 17.20±0.64 days when OVCAR-3 cells were implanted with and without SHBG, respectively (P = 0.023). The magnitude of SHBG effect depended on the age of mice and it was most prominent in the development of intraperitoneal solid tumor deposits. Levels of circulating CA-125 were also age- and tumor size-dependent. Biodistribution studies of 125 I-SHBG indicated a prolonged retention of the protein in solid tumor deposits. Estimated half-lives of 125 I-SHBG were 2.3� longer in solid tumors as compared to nonadherent cancer cells in the peritoneal lavage. The normal tissue distribution of 125 I-SHBG was similar in control and OVCAR-3-bearing mice. These data suggest that currently used models of ovarian cancer in mice, including carcinogenesis and drug evaluation studies, are imperfect because of the lack of SHBG production in these species.","PeriodicalId":89032,"journal":{"name":"The open cancer journal","volume":"2 1","pages":"59-65"},"PeriodicalIF":0.0,"publicationDate":"2008-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68050691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-12-19DOI: 10.2174/1874079000802010053
B. Tavares-Murta, E. Murta
Leukocyte migration is a key event in the inflammatory response to tumors. The tumor releases specific chemokines that control migration of leukocytes and functions of these cells after their arrival at the tumor site. In addition to these local changes in the tumor microenvironment, the host response to malignant solid tumors also gives rise to systemic effects, the most frequent of which are leukocytosis, neutrophilia and lymphopenia. These hematological findings are significantly correlated with advanced tumor stage and, therefore, poor disease prognosis. The ratio of neutrophil and lymphocyte counts has been suggested as a simple parameter of systemic inflammation in cancer patients. An elevated neutrophil to lymphocyte ratio has been shown to be an independent prognostic factor for cancers at various different sites, suggesting that this parameter is a clinically accessible and useful biomarker for patient survival. The effect of tumor development on circulating leukocyte number has not been clarified. One proposed mechanism is that tumor cells produce soluble factors such as granulocyte colony stimulating factor, which mobilize precursor cells in the bone marrow, or other mediators that alter cell differentiation. Leukocyte counts may be readily obtained at the time of diagnosis, and these data could be useful as stratification factors in clinical trials and in identifying patients with poor prognosis, leading to better treatment strategies.
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