The Hedgehog Pathway and Inflammatory Breast Cancer

刺猬通路和炎症性乳腺癌

• 批准号: 7427272
• 负责人: Kevin Peter Williams
• 金额: $ 9.71万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7427272
• 关键词: Affect; African American; Antibodies; Area; Attenuated; Automobile Driving; Biomedical Research; Biopsy Specimen; Breast Cancer Cell; Cancer Biology; Cancer Cell Growth; Cancer Patient; Cancer cell line; Cell Line; Cell Survival; Cells; Characteristics; Chemicals; Data; Detection; Development; Disease; Down-Regulation; Drug Industry; Erinaceidae; Family; Funding; Future; GH1 gene; Gene Expression; Gene Expression Profile; Genes; Goals; Grant; Growth; Human; Immunoblotting; Induction of Apoptosis; Inflammatory; Ligands; Luciferases; MYCN gene; Measures; Messenger RNA; Molecular; Pathogenesis; Pathway interactions; Patients; Polymerase Chain Reaction; Positioning Attribute; Prevalence; Procedures; Proteins; Rate; Reagent; Relapse; Reporter; Reporter Genes; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Signaling Molecule; Small Interfering RNA; Testing; Time; Woman; cancer type; career; cell growth; clinically relevant; human SMO protein; inhibitor/antagonist; insight; malignant breast neoplasm; member; mouse model; programs; protein expression; receptor; research study; small molecule; smoothened signaling pathway; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): Inflammatory breast cancer (IBC) is the most lethal form of primary breast cancer and affects African- American women disproportionately. The molecular pathways driving the pathogenesis of IBC remain poorly understood. Therefore, a better understanding of the biology of this cancer is essential for the development of more effective therapies and better detection approaches. Hedgehog (Hh) signaling has been implicated as having a truly central role in the growth of a vast array of cancer types, including breast cancer. Hedgehog signaling has not yet been studied in any detail in IBC. Preliminary data from us and other groups have identified components of the hedgehog pathway as being dysregulated in IBC. This has led to our long-term objective to elucidate the role of hedgehog signaling in inflammatory breast cancer as a prerequisite to the development of new therapies. In this application, we hypothesize that dysregulation of Hh signaling is important for the development and progression of inflammatory breast cancer and that blocking the hedgehog pathway will suppress IBC tumor growth. To test these hypotheses, we propose research with the following specific aims: Aim 1 is to determine the prevalence of expression of Hh and pathway members in IBC cell lines by real-time PCR and immunoblotting and correlate with IBC phenotypic status. Additionally, we will use a gli-luciferase reporter to measure Hh pathway activity in IBC. Aim 2 is to determine the effect of down-regulation of the Hh pathway on IBC cell viability and growth using siRNA against Hh-pathway components or by inhibiting the pathway with small molecule antagonists. The long-term future plan of these studies is to determine if Hh pathway inhibition will attenuate progression of IBC in a mouse model of the disease. Specific aim 3 is to assess the expression of Hedgehog pathway genes in human tumor biopsy samples from inflammatory breast cancer patients and to assess any correlation with tumor and patient characteristics. Inflammatory breast cancer is a devastating disease that progresses at an alarming rate. Our long-term goal is to elucidate the role of hedgehog signaling in inflammatory breast cancer as a prerequisite to the development of new therapies. In summary, in this SC2 pilot proposal, we will characterize hedgehog signaling in IBC. These studies may provide crucial insights into IBC pathogenesis that we anticipate could provide a rational target for future therapy for this fatal disease.

描述（由申请人提供）：炎性乳腺癌 (IBC) 是最致命的原发性乳腺癌，对非裔美国女性的影响尤为严重。驱动 IBC 发病机制的分子途径仍知之甚少。因此，更好地了解这种癌症的生物学对于开发更有效的疗法和更好的检测方法至关重要。 Hedgehog (Hh) 信号传导被认为在包括乳腺癌在内的多种癌症类型的生长中发挥着真正的核心作用。 IBC 中尚未对 Hedgehog 信号传导进行任何详细研究。我们和其他小组的初步数据已确定刺猬通路的组成部分在 IBC 中失调。这导致我们的长期目标是阐明刺猬信号在炎症性乳腺癌中的作用，作为开发新疗法的先决条件。 在本申请中，我们假设 Hh 信号传导失调对于炎性乳腺癌的发生和进展很重要，并且阻断 Hedgehog 通路将抑制 IBC 肿瘤生长。为了检验这些假设，我们提出以下具体目标的研究：目标 1 是通过实时 PCR 和免疫印迹确定 IBC 细胞系中 Hh 和通路成员表达的流行率，并与 IBC 表型状态相关联。此外，我们将使用 gli-荧光素酶报告基因来测量 IBC 中的 Hh 通路活性。目标 2 是使用针对 Hh 途径成分的 siRNA 或通过使用小分子拮抗剂抑制该途径来确定 Hh 途径下调对 IBC 细胞活力和生长的影响。这些研究的长期未来计划是确定 Hh 通路抑制是否会减弱 IBC 小鼠模型中的进展。具体目标 3 是评估来自炎性乳腺癌患者的人类肿瘤活检样本中 Hedgehog 通路基因的表达，并评估与肿瘤和患者特征的任何相关性。炎性乳腺癌是一种毁灭性的疾病，其进展速度惊人。我们的长期目标是阐明刺猬信号在炎症性乳腺癌中的作用，作为开发新疗法的先决条件。总之，在这个 SC2 试点提案中，我们将描述 IBC 中刺猬信令的特征。这些研究可能为 IBC 发病机制提供重要的见解，我们预计这可以为这种致命疾病的未来治疗提供合理的目标。