Pub Date : 2015-10-01DOI: 10.23937/2378-3419/2/4/1023
Peter O. Oladimeji, Y. Kubohara, H. Kikuchi, Y. Oshima, Courtney Rusch, Rebekah Skerl, M. Diakonova
Differentiation-inducing factors 1-3 (DIFs 1-3), chlorinated alkylphenones identified in the cellular slime mold Dictyostelium discoideum, are considered anti-tumor agents because they inhibit proliferation of a variety of mammalian tumor cells in vitro. Although the anti-proliferative effects of DIF-1 and DIF-3 are well-documented, the precise molecular mechanisms underlying the actions of DIFs have not been fully elucidated. In this study, we examined the effects of DIFs and their derivatives on PAK1, a key serine-threonine kinase, which is activated by multiple ligands and regulates cell proliferation. We examined the effect of DIF derivatives on PAK1 kinase activity in cells. We also examined the effect of DIF-3(+1) derivative on PAK1 kinase activity in vitro, cyclin D1 promoter activity and breast cancer cell proliferation. It was found that some derivatives strongly inhibited PAK1 kinase activity in human breast cancer MCF-7 cells stably over expressing PAK1. Among the derivatives, DIF-3(+1) was most potent, which directly inhibited kinase activity of recombinant purified PAK1 in an in vitro kinase assay. Furthermore, DIF-3(+1) strongly inhibited both cyclin D1 promoter activity and proliferation of MCF-7 and T47D breast cancer cells stably over expressing PAK1 in response to prolactin, estrogen, epidermal growth factor and heregulin. In the present study we propose PAK1 as DIF-3(+1) target mediating its anti-proliferative effect.
{"title":"A Derivative of Differentiation-Inducing Factor-3 Inhibits PAK1 Activity and Breast Cancer Cell Proliferation","authors":"Peter O. Oladimeji, Y. Kubohara, H. Kikuchi, Y. Oshima, Courtney Rusch, Rebekah Skerl, M. Diakonova","doi":"10.23937/2378-3419/2/4/1023","DOIUrl":"https://doi.org/10.23937/2378-3419/2/4/1023","url":null,"abstract":"Differentiation-inducing factors 1-3 (DIFs 1-3), chlorinated alkylphenones identified in the cellular slime mold Dictyostelium discoideum, are considered anti-tumor agents because they inhibit proliferation of a variety of mammalian tumor cells in vitro. Although the anti-proliferative effects of DIF-1 and DIF-3 are well-documented, the precise molecular mechanisms underlying the actions of DIFs have not been fully elucidated. In this study, we examined the effects of DIFs and their derivatives on PAK1, a key serine-threonine kinase, which is activated by multiple ligands and regulates cell proliferation. We examined the effect of DIF derivatives on PAK1 kinase activity in cells. We also examined the effect of DIF-3(+1) derivative on PAK1 kinase activity in vitro, cyclin D1 promoter activity and breast cancer cell proliferation. It was found that some derivatives strongly inhibited PAK1 kinase activity in human breast cancer MCF-7 cells stably over expressing PAK1. Among the derivatives, DIF-3(+1) was most potent, which directly inhibited kinase activity of recombinant purified PAK1 in an in vitro kinase assay. Furthermore, DIF-3(+1) strongly inhibited both cyclin D1 promoter activity and proliferation of MCF-7 and T47D breast cancer cells stably over expressing PAK1 in response to prolactin, estrogen, epidermal growth factor and heregulin. In the present study we propose PAK1 as DIF-3(+1) target mediating its anti-proliferative effect.","PeriodicalId":13873,"journal":{"name":"International journal of cancer and clinical research","volume":"6 1","pages":"1 - 6"},"PeriodicalIF":0.0,"publicationDate":"2015-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86695662","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 : 2015-01-01DOI: 10.23937/2378-3419/2/1/1013
Lauren E McCullough, Jia Chen, Alexandra J White, Xinran Xu, Yoon Hee Cho, Patrick T Bradshaw, Sybil M Eng, Susan L Teitelbaum, Mary Beth Terry, Gail Garbowski, Alfred I Neugut, Hanina Hibshoosh, Regina M Santella, Marilie D Gammon
Introduction: Breast cancer, the leading cancer diagnosis among American women, is positively associated with postmenopausal obesity and little or no recreational physical activity (RPA). However, the underlying mechanisms of these associations remain unresolved. Aberrant changes in DNA methylation may represent an early event in carcinogenesis, but few studies have investigated associations between obesity/RPA and gene methylation, particularly in postmenopausal breast tumors where these lifestyle factors are most relevant.
Methods: We used case-case unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the associations between body mass index (BMI=weight [kg]/height [m2]) in the year prior to diagnosis, or RPA (average hours/week), and methylation status (methylated vs. unmethylated) of 13 breast cancer-related genes in 532 postmenopausal breast tumor samples from the Long Island Breast Cancer Study Project. We also explored whether the association between BMI/RPA and estrogen/progesterone-receptor status (ER+PR+ vs. all others) was differential with respect to gene methylation status. Methylation-specific PCR and the MethyLight assay were used to assess gene methylation.
Results: BMI 25-29.9kg/m2, and perhaps BMI≥30kg/m2, was associated with methylated HIN1 in breast tumor tissue. Cases with BMI≥30kg/m2 were more likely to have ER+PR+ breast tumors in the presence of unmethylated ESR1 (OR=2.63, 95% CI 1.32-5.25) and women with high RPA were more likely to have ER+PR+ breast tumors with methylated GSTP1 (OR=2.33, 95% CI 0.79-6.84).
Discussion: While biologically plausible, our findings that BMI is associated with methylated HIN1 and BMI/RPA are associated with ER+PR+ breast tumors in the presence of unmethylated ESR1 and methylated GSTP1, respectively, warrant further investigation. Future studies would benefit from enrolling greater numbers of postmenopausal women and examining a larger panel of breast cancer-related genes.
乳腺癌是美国女性的主要癌症诊断，与绝经后肥胖和很少或没有娱乐性体育活动(RPA)呈正相关。然而，这些关联的潜在机制仍未得到解决。DNA甲基化的异常变化可能代表了癌变的早期事件，但很少有研究调查肥胖/RPA和基因甲基化之间的关系，特别是在绝经后乳腺肿瘤中，这些生活方式因素是最相关的。方法:我们使用病例-病例无条件逻辑回归来估计长岛乳腺癌研究项目532例绝经后乳腺癌样本中诊断前一年体重指数(BMI=体重[kg]/身高[m2])或RPA(平均小时数/周)与13种乳腺癌相关基因甲基化状态(甲基化与未甲基化)之间的比值比(ORs)和95%置信区间(CI)。我们还探讨了BMI/RPA与雌激素/孕激素受体状态(ER+PR+ vs.所有其他)之间的关联是否与基因甲基化状态有关。甲基化特异性PCR和MethyLight检测用于评估基因甲基化。结果:BMI 25-29.9kg/m2, BMI≥30kg/m2可能与乳腺肿瘤组织中HIN1甲基化相关。BMI≥30kg/m2的患者在ESR1未甲基化的情况下更容易发生ER+PR+乳腺肿瘤(OR=2.63, 95% CI 1.32-5.25)，高RPA的女性更容易发生ER+PR+乳腺肿瘤并甲基化GSTP1 (OR=2.33, 95% CI 0.79-6.84)。讨论:虽然生物学上是合理的，但我们的研究结果表明BMI与甲基化的HIN1相关，BMI/RPA分别与未甲基化的ESR1和甲基化的GSTP1存在的ER+PR+乳腺肿瘤相关，值得进一步研究。未来的研究将受益于招募更多的绝经后妇女和检查更多的乳腺癌相关基因。
{"title":"Gene-Specific Promoter Methylation Status in Hormone-Receptor-Positive Breast Cancer Associates with Postmenopausal Body Size and Recreational Physical Activity.","authors":"Lauren E McCullough, Jia Chen, Alexandra J White, Xinran Xu, Yoon Hee Cho, Patrick T Bradshaw, Sybil M Eng, Susan L Teitelbaum, Mary Beth Terry, Gail Garbowski, Alfred I Neugut, Hanina Hibshoosh, Regina M Santella, Marilie D Gammon","doi":"10.23937/2378-3419/2/1/1013","DOIUrl":"https://doi.org/10.23937/2378-3419/2/1/1013","url":null,"abstract":"<p><strong>Introduction: </strong>Breast cancer, the leading cancer diagnosis among American women, is positively associated with postmenopausal obesity and little or no recreational physical activity (RPA). However, the underlying mechanisms of these associations remain unresolved. Aberrant changes in DNA methylation may represent an early event in carcinogenesis, but few studies have investigated associations between obesity/RPA and gene methylation, particularly in postmenopausal breast tumors where these lifestyle factors are most relevant.</p><p><strong>Methods: </strong>We used case-case unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the associations between body mass index (BMI=weight [kg]/height [m<sup>2</sup>]) in the year prior to diagnosis, or RPA (average hours/week), and methylation status (methylated vs. unmethylated) of 13 breast cancer-related genes in 532 postmenopausal breast tumor samples from the Long Island Breast Cancer Study Project. We also explored whether the association between BMI/RPA and estrogen/progesterone-receptor status (ER+PR+ vs. all others) was differential with respect to gene methylation status. Methylation-specific PCR and the MethyLight assay were used to assess gene methylation.</p><p><strong>Results: </strong>BMI 25-29.9kg/m<sup>2</sup>, and perhaps BMI≥30kg/m<sup>2</sup>, was associated with methylated <i>HIN1</i> in breast tumor tissue. Cases with BMI≥30kg/m<sup>2</sup> were more likely to have ER+PR+ breast tumors in the presence of unmethylated <i>ESR1</i> (OR=2.63, 95% CI 1.32-5.25) and women with high RPA were more likely to have ER+PR+ breast tumors with methylated <i>GSTP1</i> (OR=2.33, 95% CI 0.79-6.84).</p><p><strong>Discussion: </strong>While biologically plausible, our findings that BMI is associated with methylated <i>HIN1</i> and BMI/RPA are associated with ER+PR+ breast tumors in the presence of unmethylated <i>ESR1</i> and methylated <i>GSTP1</i>, respectively, warrant further investigation. Future studies would benefit from enrolling greater numbers of postmenopausal women and examining a larger panel of breast cancer-related genes.</p>","PeriodicalId":13873,"journal":{"name":"International journal of cancer and clinical research","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440485/pdf/nihms-683885.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33332472","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 : 1900-01-01DOI: 10.23937/2378-3419/1410150
Shah Manan, Oprea Gabriela, Shafia Saba, Surapaneni Phani Keerthi, Sasidharan Sandeep, J. Sanjay
{"title":"Prognostic Significance of Hormone Receptor (ER/PR) Status Inendometrial Carcinoma in Black Women: Implications with Lymph Node Metastasis","authors":"Shah Manan, Oprea Gabriela, Shafia Saba, Surapaneni Phani Keerthi, Sasidharan Sandeep, J. Sanjay","doi":"10.23937/2378-3419/1410150","DOIUrl":"https://doi.org/10.23937/2378-3419/1410150","url":null,"abstract":"","PeriodicalId":13873,"journal":{"name":"International journal of cancer and clinical research","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78827511","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}
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