The Hedgehog Pathway and Inflammatory Breast Cancer

描述（由申请人提供）：炎症性乳腺癌（IBC）是原发性乳腺癌中最致命的形式，对非洲裔美国妇女的影响尤为严重。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治疗方法和更好的检测方法至关重要。Hedgehog （Hh）信号被认为在包括乳腺癌在内的大量癌症类型的生长中具有真正的核心作用。刺猬信号传导在IBC中尚未得到详细研究。我们和其他小组的初步数据已经确定了在IBC中hedgehog通路的成分失调。这导致我们的长期目标是阐明刺猬信号在炎性乳腺癌中的作用，作为开发新疗法的先决条件。

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.