The Hedgehog Pathway and Inflammatory Breast Cancer

描述（由申请人提供）：炎性乳腺癌（IBC）是原发性乳腺癌中最致命的形式，对非裔美国妇女的影响不成比例。驱动IBC发病机制的分子途径仍然知之甚少。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）信号转导被认为在包括乳腺癌在内的大量癌症类型的生长中发挥了真正的核心作用。Hedgehog信号尚未在IBC中进行任何详细研究。我们和其他研究小组的初步数据已经确定了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。 在本申请中，我们假设Hh信号传导的失调对于炎性乳腺癌的发展和进展是重要的，并且阻断hedgehog通路将抑制IBC肿瘤生长。为了验证这些假设，我们提出了以下具体目标的研究：目的1是通过实时PCR和免疫印迹确定IBC细胞系中Hh和途径成员表达的流行率，并与IBC表型状态相关。此外，我们将使用gli-荧光素酶报告基因来测量IBC中的Hh途径活性。目的2是使用针对Hh途径组分的siRNA或通过用小分子拮抗剂抑制该途径来确定Hh途径的下调对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途径抑制是否会减弱疾病小鼠模型中IBC的进展。具体目标3是评估Hedgehog途径基因在来自炎性乳腺癌患者的人肿瘤活检样品中的表达，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以惊人的速度发展的毁灭性疾病。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中的刺猬信号。这些研究可能为IBC的发病机制提供重要的见解，我们预计可以为这种致命疾病的未来治疗提供合理的靶点。

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.