Epigenetics of the Retinoic Acid Paradox

视黄酸悖论的表观遗传学

• 批准号: 7577356
• 负责人: NICOLETTA SACCHI
• 金额: $ 34.27万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7577356
• 关键词: All-Trans-Retinol; Animals; Beta Carotene; Breast; Breast Cancer Cell; Breast Cancer Treatment; Cell Line; Cell model; Cells; Ceramides; Cessation of life; Chemoprevention; Data; Disease; Epigenetic Process; Epithelial; Epithelial Cells; Face; Gene Expression Regulation; Growth; Hand; Impairment; In Vitro; Inbred HRS Mice; Incidence; Intestinal Neoplasms; Lead; Literature; Maintenance; Malignant Neoplasms; Mammary Tumorigenesis; Mediating; Outcome Study; PPAR-beta; Pathway interactions; Phenotype; Plants; Pre-Clinical Model; Predisposition; Prevention; Protein Kinase C Alpha; Receptor Signaling; Regulation; Retinoic Acid Receptor; Signal Pathway; Signal Transduction; Skin Carcinogenesis; Source; Sphingolipids; Staging; TGFBR2 gene; Testing; Therapeutic Clinical Trial; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transgenic Model; Transgenic Organisms; Tretinoin; Tumor Promoters; Tumor Promotion; Tumor Suppressor Proteins; UV induced; Vitamin A; Work; cancer cell; cancer prevention; cell growth; common treatment; discount; drug testing; in vivo; inhibitor/antagonist; malignant breast neoplasm; mouse model; preclinical study; receptor; response; retinoic acid receptor alpha; retinoic acid receptor beta 2; sphingosine 1-phosphate; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Retinoic acid (RA), from dietary sources of Vitamin A, is a potent inhibitor of cell and tumor growth. As such, RA has been considered for chemoprevention and therapy of epithelial cancer. However, contradictory responses to RA and its precursors in both preclinical models and chemoprevention/therapeutic clinical trials imply that RA can have a dual face: in some contexts it can act as a tumor inhibitor, in others as a tumor promoter. Literature data and our preliminary work indicate that an impaired RA signal through the RA receptor alpha (RARA) in both untransformed and transformed breast cancer cells leads to variegated and paradoxical effects implicating one, or more, prosurvival and prometastatic signaling pathway such as the TGFB and Sphingosine 1 Phosphate (S1P) pathways, and pathways governed by non-RAR targets capable of interacting directly with RA, such as the Protein Kinase C alpha (PKCA) and PPAR beta/delta (PPARD) pathways. We hypothesize that: Loss/impairment of RA-RARA- mediated epigenetic regulation due to upstream intrinsic/extrinsic factors makes RA activate, via non-RAR-targets, one, or more, tumor-promoting signaling pathways. To expand on this hypothesis we propose to combine in vitro and in vivo breast cancer cell models and mechanistic approaches to: identify candidate factors that can lead to loss/impairment of RA-RAR-mediated epigenetic regulation thus causing breast cancer tumor progression (Aim 1); understand whether TGFBR2 epigenetic silencing, consequent to impaired RA-RAR signaling, contributes to RA-induced tumor progression (Aim 2); further test whether the S1P signaling contributes to RA-induced survival in vivo, and test for drugs that can counteract this effect (Aim 3); mechanistically test whether, in the absence of RARA, and its downstream RAR targets, RA exerts its tumor promoting action through non-RAR targets such as PKCA and PPARD (Aim 4). The outcome of these studies is expected to impact prevention and treatment of breast cancer, at early, as well as late stages. PUBLIC HEALTH RELEVANCE: Retinoic acid (RA), from dietary sources of Vitamin A, is a potent inhibitor of cell and tumor growth. As such, RA has been considered for chemoprevention and therapy of epithelial cancer. However, contradictory responses to RA and its precursors in both preclinical models and chemoprevention/therapeutic clinical trials imply that RA can have a dual face: in some contexts it can act as a tumor inhibitor, in others as a tumor promoter. We found in our preliminary studies that impairment of RA-signal through canonical RA receptors (RARs) on one hand abrogates epigenetic regulation of RAR- targets and on the other hand activates via as yet unidentified non-RARs one, or more, tumor-promoting signaling pathways. To expand on this hypothesis we propose four specific aims to combine in vitro and in vivo breast cancer cell models and mechanistic approaches to identify candidate factors that can lead to loss/impairment of RA-RAR- mediated epigenetic regulation thus causing breast cancer tumor progression. The outcome of these studies is expected to impact prevention and treatment of breast cancer, at early, as well as late stages.

描述（由申请人提供）： 维生素A饮食来源的视黄酸（RA）是细胞和肿瘤生长的有效抑制剂。因此，已考虑将RA用于上皮癌的化学预防和治疗。但是，在临床前模型和化学预防/治疗性临床试验中，对RA及其前体的反应矛盾，这意味着RA可以具有双重面孔：在某些情况下，它可以作为肿瘤抑制剂，在其他情况下作为肿瘤启动子。文献数据和我们的初步工作表明，在未转换和转化的乳腺癌细胞中，通过RA受体α（RARA）通过RA受体α（RARA）信号会导致多样化和矛盾的效应，与一个或更多的抗性效应有关，涉及一个或更多的prosetastastatic和Prometastatic的信号，例如与TGFB和Sphingosine 1磷酸盐（s1p）的靶向途径（s1p），并与s1 pation patherage（S1 P）相互作用。 RA，例如蛋白激酶Cα（PKCA）和PPAR Beta/Delta（PPARD）途径。我们假设这是：由于上游固有/外部因素引起的RA-RARA介导的表观遗传调节的损失/损害使RA通过非靶标，一个或更多或更多的肿瘤促进信号通路激活。为了扩展这一假设，我们建议将体外和体内乳腺癌细胞模型和机械方法结合起来：确定可以导致RA-RAR介导的表观遗传学调节损失/损害的候选因素，从而导致乳腺癌肿瘤的进展（AIM 1）；了解TGFBR2表观遗传沉默是否会导致RA-RAR信号传导，导致RA诱导的肿瘤进展（AIM 2）；进一步测试S1P信号是否有助于RA诱导的体内生存，并测试可以抵消这种作用的药物（AIM 3）；机械师地测试在没有RARA的情况下，RA是否通过诸如PKCA和PPARD之类的非强靶靶标（AIM 4）促进其肿瘤促进作用。这些研究的结果有望在早期以及晚期影响乳腺癌的预防和治疗。公共卫生相关性：维生素A饮食来源的视黄酸（RA）是细胞和肿瘤生长的有效抑制剂。因此，已考虑将RA用于上皮癌的化学预防和治疗。但是，在临床前模型和化学预防/治疗性临床试验中，对RA及其前体的反应矛盾，这意味着RA可以具有双重面孔：在某些情况下，它可以作为肿瘤抑制剂，在其他情况下作为肿瘤启动子。我们在初步研究中发现，一方面通过规范的RA受体（RARS）损害了RA信号，一方面消除了稀有靶标的表观遗传调节，另一方面，通过尚未确定的非识别的非差异或更多的是肿瘤促进信号途径激活。为了扩展这一假设，我们提出了四个特定的目的，以结合体外和体内乳腺癌细胞模型和机械方法，以鉴定候选因素，这些因素可能导致RA-rar-介导的表观遗传调节的损失/损害，从而导致乳腺癌肿瘤的进展。这些研究的结果有望在早期以及晚期影响乳腺癌的预防和治疗。