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）：炎症性乳腺癌（IBC）是原发性乳腺癌最致命的形式，对非裔美国妇女的影响不成比例。驱动IBC发病机理的分子途径仍然很少理解。因此，更好地了解该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。刺猬（HH）信号被暗示是在包括乳腺癌在内的各种癌症类型的生长中具有真正的核心作用。 IBC中尚未对刺猬信号进行任何详细研究。来自我们和其他组的初步数据已经确定了刺猬途径的组成部分，在IBC中均失调。这导致了我们的长期目标，以阐明刺猬信号在炎症性乳腺癌中的作用，这是发展新疗法的先决条件。 在此应用中，我们假设HH信号传导失调对于炎症性乳腺癌的发展和进展至关重要，而阻止刺猬途径将抑制IBC肿瘤的生长。为了检验这些假设，我们提出了以下具体目的的研究：目标1是通过实时PCR和免疫印迹和与IBC表型状态相关的IBC细胞系中HH和途径成员表达的普遍性。此外，我们将使用Gli-luciferase Reporter测量IBC中的HH途径活性。 AIM 2是确定HH途径下调对IBC细胞活力和使用siRNA对HH-PATHWAY组件的生长的影响，或者通过抑制小分子拮抗剂的途径。这些研究的长期未来计划是确定HH途径抑制是否会在疾病的小鼠模型中减轻IBC的进展。具体目的3是评估炎症性乳腺癌患者的人类肿瘤活检样本中刺猬途径基因的表达，并评估与肿瘤和患者特征的任何相关性。炎症性乳腺癌是一种毁灭性疾病，以惊人的速度发展。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，这是发展新疗法的先决条件。总而言之，在此SC2试点建议中，我们将在IBC中表征刺猬信号。这些研究可能会提供对IBC发病机理的关键见解，我们预计我们可以为这种致命疾病的未来治疗提供一个合理的靶标。