The Hedgehog Pathway and Inflammatory Breast Cancer

描述(由申请人提供)：炎症性乳腺癌(IBC)是最致命的原发乳腺癌，对非裔美国女性的影响不成比例。IBC发病机制的分子机制仍知之甚少。因此，更好地了解这种癌症的生物学对于开发更有效的治疗方法和更好的检测方法是至关重要的。Hedgehog(HH)信号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还没有对刺猬信号进行任何详细的研究。来自美国和其他研究小组的初步数据已经确定，刺猬途径的组成部分在IBC中处于失调状态。这使得我们的长期目标是阐明Hedgehog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。 在这个应用中，我们假设HH信号的失调在炎症性乳腺癌的发生和发展中是重要的，并且阻断Hedgehog通路将抑制IBC肿瘤的生长。为了验证这些假说，我们提出了具有以下特定目的的研究：目的1通过实时定量聚合酶链式反应和免疫印迹法确定HH及其通路成员在IBC细胞系中的表达情况，并与IBC表型状态相关联。此外，我们将使用Gi-荧光素酶报告程序来测量IBC中HH途径的活性。目的2是利用针对HH通路组分的siRNA或小分子拮抗剂抑制HH通路，以确定HH通路下调对IBC细胞存活和生长的影响。这些研究的长期未来计划是确定抑制HH途径是否会减缓该病小鼠模型的IBC进展。具体目标3是评估Hedgehog通路基因在炎症性乳腺癌患者的肿瘤活检样本中的表达，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的疾病，进展速度惊人。我们的长期目标是阐明Hedgehog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中的刺猬信令的特征。这些研究可能会对IBC的发病机制提供重要的见解，我们预计可能会为这种致命疾病的未来治疗提供一个合理的靶点。

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.