Mechanisms Regulating Reversal of Malignancy

恶性肿瘤逆转的调节机制

• 批准号: 7939057
• 负责人: Priscilla A. Furth
• 金额: $ 9.69万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939057
• 关键词: Agonist; Back; Biochemical; Biological Markers; Breast; CDK2 gene; Catalytic Domain; Cell Cycle Arrest; Collagen; Complex; Confocal Microscopy; Cyclin D1; Cyclins; Development; Diet; Differentiation Therapy; Disease; Disseminated Malignant Neoplasm; Dose; Down-Regulation; Dysplasia; Epithelial Cells; Estrogen Receptor alpha; Event; Extracellular Matrix; Failure; Genes; Genetic Transcription; Goals; Histologic; Human; Image Analysis; Imaging technology; In Situ; Interruption; Intraductal Hyperplasia; Lead; Ligands; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of salivary gland; Mammary gland; Mediating; Modeling; Molecular; Molecular Genetics; Molecular Sequence Alteration; Mus; Noninfiltrating Intraductal Carcinoma; Nuclear Receptors; PPAR gamma; Pathway interactions; Phase; Phosphoric Monoester Hydrolases; Phosphorylation; Premalignant; Principal Investigator; Process; Production; Progesterone Receptors; Protein phosphatase; RXR; Refractory; Research Personnel; Resistance; Resolution; Retinoid X Receptor alpha; Role; Salivary; Salivary Glands; Secondary to; Staging; TP53 gene; Tamoxifen; Techniques; Testing; Therapeutic; Time; Tissues; Transgenes; Translating; Treatment Protocols; Tumor Suppressor Genes; Up-Regulation; Woman; cancer prevention; comparative efficacy; cyclin G; gene repression; in vivo; loss of function; malignant breast neoplasm; mouse model; novel; prevent; programs; research study; response; response marker; rosiglitazone; treatment program; tumor progression

DESCRIPTION (provided by applicant): Our long-range goal is to establish the mechanisms underlying successful therapeutic approaches to reverse preneoplasia, identify genetic and molecular events that impair reversal, identify predictive biomarkers and translate results to people. This Project will exploit unique conditional mouse models of breast and salivary gland cancer to define the role of p53 in pharmacological differentiation therapies that target nuclear receptors Retinoid X Receptor alpha (RXRalpha) and Peroxisome proliferator-activated receptor gamma (PPARgamma). Reversal of premalignant disease is one goal of cancer prevention treatment programs. Interruption of the malignant process at an early stage is preferable to treating the fully developed and perhaps metastatic cancer. The central hypothesis of this proposal is that ligand induced activation of RXRalpha and PPARgamma in epithelial cells can impel resolution of refractory dysplasia through a re-differentiation process that involves down-regulation of Protein Phosphatase 2A (PP2A) activity. A secondary hypothesis is that normal p53 function contributes to the re-differentiation process initiated by RXRalpha and/or PPARgamma agonists. Hypothesis: The mechanism by which pharmacological activation of RXRalpha and/or PPARgamma in epithelial cell preneoplasia in vivo leads to successful disease reversal is through cell cycle arrest and differentiation mediated by down- regulation of PP2Ac, DP-1 phosphorylation, decreased CDK-2, increased p27, increased p53 activity, and decreased collagen production with changes in the extracelllalr matrix. Additional mechanisms that will be activated in ERalpha positive mammary preneoplasia include down-regulation of ERalpha and cyclin D1, up- regulation of Brca1 and decreased collagen production with changes in the extracellular matrix. Specific Aims: 1. a. Test if pharmacological RXRalpha and/or PPARgamma agonists alone or in combination are able to redifferentiate refractory dysplastic salivary tissue in GRIDS mice through down-regulation of PP2Ac expression with secondary gain of DP-1 phosphorylation, loss of CDK-2, and increased p27 expression. 1. b. Test if normal p53 expression levels contribute to successful reversal by these pharmacological agents. 2. a. Test if pharmacological RXRalpha and/or PPARgamma agonists alone or in combination redifferentiate ERalpha-expressing ductal hyperplasia and DCIS in CERM mice through down-regulation of PP2Ac, gain of DP-1 phosphorylation, increased p27 and loss of CDK-2 and/or through loss of ERalpha, cyclin D1 and increased Brca1. Compare histological and molecular responses to the RXRalpha and/or PPARgamma agonists with the ERalpha antagonist tamoxifen and conditional down-regulation of the ERalpha transgene. 2. b. Test if normal p53 expression contributes to successful reversal by pharmacological RXR and/or PPARgamma agonists, the ERalpha antagonist tamoxifen and/or conditional down-regulation of the ERalpha transgene. 2. c. Test if pharmacological RXRalpha and/or PPARgamma agonists alone or in combination prevent development of ERalpha ductal hyperplasia and DCIS.

描述（由申请人提供）：我们的远程目标是建立成功的治疗方法的基础机制，以逆转质激素，确定遗传和分子事件，以损害逆转，识别预测性生物标志物并将结果转化为人们。该项目将利用乳腺癌和唾液腺癌的独特有条件小鼠模型来定义p53在靶向核受体X受体X受体α（RXRALPHA）和过氧化物酶体增殖物激活受体Gamma（Ppargamma）中的药理分化疗法中的作用。逆转疾病的逆转是预防癌症治疗计划的目标之一。早期的恶性过程中断比治疗完全发育和转移性癌症是可取的。该提案的中心假设是，配体在上皮细胞中诱导的rxralpha和ppargamma激活可以通过涉及下调蛋白质磷酸酶2a（pp2a）活性下调的重新分化过程，从而促进难治性异常增生。次要假设是正常的p53函数有助于由rxralpha和/或ppargamma激动剂引发的重新分化过程。假设：在体内上皮细胞质质质量中rxralpha和/或ppargamma的药理学激活的机制导致成功疾病的成功疾病逆转是通过细胞周期停滞和通过PP2AC的下降介导的PP2AC介导的介导的PP2AC，DP-1磷酸化，DP-1磷酸化，DP-1磷酸化，减少CDK-2的生产，并增加了P27，并减少了P27，并减少了P27活动，并降低了P53活动的变化，并降低了P53活动的变化。 矩阵。在Eralpha阳性乳腺肿瘤中将激活的其他机制包括对Eralpha和Cyclin D1的下调，BRCA1的上调节以及胶原蛋白产生的降低以及细胞外基质的变化。具体目的：1。a。测试药理学rxralpha和/或Ppargamma激动剂是否单独或组合能够通过下调PP2AC表达，并通过DP-1磷酸化的继发性增长，CDK-2的损失和P27表达增加，可以通过pp2AC表达下降，并通过下调PP2AC表达来重新分化难治性的唾液组织。 1。b。测试是否正常的p53表达水平有助于这些药理学剂的成功逆转。 2。测试是否单独进行药理学rxralpha和/或ppargamma激动剂，或组合通过pp2ac的下调，DP-1磷酸化的增加，p27的增加，p27增加，p27和或通过CDK-2和/OR损失，通过下调PP2AC，通过下调PP2AC来重新分化表达ERALPHA的导管增生和DCI。将组织学和分子对rxralpha和/或ppargamma激动剂的反应与eralpha拮抗剂的tamoxifen以及Eralpha转基因的条件下调。 2。b。测试如果正常的p53表达有助于通过药理学RXR和/或ppargamma激动剂，Eralpha拮抗剂他莫昔芬和/或有条件的Eralpha transgene下调。 2。c。测试药理学rxralpha和/或ppargamma激动剂，还是结合使用Eralpha导管增生和DCIS的发展。

项目成果

What do shifts in indicators of apoptosis indicate about the cancer process?

细胞凋亡指标的变化表明癌症的发展过程是什么？

• DOI: 10.1093/jn/136.10.2700s
• 发表时间: 2006
• 期刊: The Journal of nutrition
• 作者: Furth,PriscillaA;Halama,EwaD
• 通讯作者: Halama,EwaD

Cancer prevention as biomodulation: targeting the initiating stimulus and secondary adaptations.

作为生物调节的癌症预防：针对起始刺激和二次适应。

• DOI: 10.1111/j.1749-6632.2012.06736.x
• 发表时间: 2012
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Furth,PriscillaA

Methoxychlor induces atresia of antral follicles in ERalpha-overexpressing mice.

甲氧滴滴涕诱导 ERalpha 过表达小鼠的窦卵泡闭锁。

• DOI: 10.1093/toxsci/kfl040
• 发表时间: 2006
• 期刊: Toxicological sciences : an official journal of the Society of Toxicology.
• 作者: Tomic,Dragana;Frech,MariaSilvina;Babus,JaniceK;Gupta,RupeshK;Furth,PriscillaA;Koos,RobertD;Flaws,JodiA
• 通讯作者: Flaws,JodiA

Deregulated estrogen receptor alpha expression in mammary epithelial cells of transgenic mice results in the development of ductal carcinoma in situ.

• DOI: 10.1158/0008-5472.681.65.3
• 发表时间: 2005-02
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: M. S. Frech;E. Halama;M. Tilli;Baljit Singh;Baljit Singh;E. Gunther;L. Chodosh;J. Flaws;P. Furth

Effects of ERalpha overexpression on female reproduction in mice.

ERalpha 过度表达对雌性小鼠生殖的影响。

• DOI: 10.1016/j.reprotox.2006.08.004
• 发表时间: 2007
• 期刊: Reproductive toxicology (Elmsford, N.Y.)
• 作者: Tomic,Dragana;Frech,MariaSilvina;Babus,JaniceK;Symonds,Daniel;Furth,PriscillaA;Koos,RobertD;Flaws,JodiA
• 通讯作者: Flaws,JodiA