miR-200c Mediates Suppression of Anoikis Resistance by Targeting an Autocrine Sig

描述（由申请人提供）：该项目的长期目标是为传统化疗无反应或复发的三阴性乳腺癌患者确定一种新的治疗方法。由于缺乏激素受体，患有这种特殊亚型乳腺癌的患者的治疗选择极为有限。因此，确定驱动这种癌症的分子机制和确定新的治疗策略是当务之急。我的实验室和其他人的初步数据表明，miR-200c抑制迁移、侵袭、对微管靶向药物的抗性和癌症干细胞表型。我已经证明，将miR-200c恢复到三阴性乳腺癌细胞系中也会抑制它们对肿瘤的抗性。Anoikis是细胞凋亡的一种形式，当细胞失去与细胞外基质的相互作用时，它被认为是转移的生理屏障。当癌细胞在脉管系统或淋巴管中形成栓子，但被剥夺了基质的粘附性时，对anoikis的抵抗力可能允许癌细胞在体循环中存活。我发现miR-200c直接靶向多种癌症类型中涉及anoikis耐药的细胞表面受体，即神经营养酪氨酸受体激酶B （TrkB）。此外，TrkB的配体神经营养因子3 （NTF3）在3' UTR中有2个预测miR-200c结合位点。综上所述，这些数据导致了我的假设，即miR-200c通过靶向TrkB/NTF3信号通路增强了anoikis在乳腺癌细胞中的敏感性。以下具体目标验证了这一假设。具体目的1：确定TrkB/NTF3中的自分泌信号环是否有助于miR- 200c抑制乳腺癌细胞的anoikis抗性。具体目的2：确定乳腺癌患者样本中miR-200c的缺失是否与TrkB和NTF3的表达相关。具体目的3：在体内研究miR- 200c对侵袭性乳腺癌细胞的致敏能力

DESCRIPTION (provided by applicant): The long-term goal of this project is to identify a new treatment for patients with triple negative breast cancer who have not responded to, or relapsed while on, traditional chemotherapeutics. Patients with this particular subtype of breast cancer have extremely limited therapeutic options due to the absence of hormone receptors. Thus, determining the molecular mechanisms that drive this cancer and identifying new therapeutic strategies is a high priority. Preliminary data from my lab and others demonstrates that miR-200c suppresses migration, invasion, resistance to microtubule targeting agents and a cancer stem cell phenotype. I have demonstrated that restoring miR-200c to triple negative breast cancer cell lines also suppresses their resistance to anoikis. Anoikis is a form of apoptosis that is initiated when the cells lose their interactions with the extracellular matrix, and it has been suggested as a physiological barrier to metastasis. Resistance to anoikis may allow survival of the carcinoma cells during systemic circulation, when they form emboli in the vasculature or lymphatics but are deprived of matrix adhesion. I have found that miR-200c directly targets a cell surface receptor implicated in anoikis resistance in multiple cancer types, neurotrophic tyrosine receptor kinase B (TrkB). Furthermore, neurotrophin 3 (NTF3), a ligand for TrkB has 2 predicted miR-200c binding sites in the 3' UTR. Taken together, this data leads to my hypothesis that miR-200c enhances anoikis sensitivity in breast cancer cells through targeting of a TrkB/NTF3 signaling pathway. The following specific aims test this hypothesis. Specific aim 1: Determine if an autocrine signaling loop in TrkB/NTF3 contributes to the ability of miR- 200c to suppress anoikis resistance in breast cancer cells. Specific aim 2: Determine if loss of miR-200c correlates with expression of TrkB and NTF3 in breast cancer patient samples. Specific aim 3: Study the ability of miR- 200c to sensitize aggressive breast cancer cells to anoikis in an in vivo model of metastasis. By furthering our understanding of how miR-200c affects anoikis resistance in breast cancer, we move closer to the development of this influential miRNA as a therapeutic option. PUBLIC HEALTH RELEVANCE: Breast cancer is the second most deadly cancer a woman will face in her lifetime, with no real treatment options for patients with triple negative breast cancer who do not respond to, or relapse while on, traditional chemotherapy. We have identified a miRNA, miR-200c, that is able to sensitize cells to an inherent cellular program that drives them to die when they are unattached. By utilizing miR-200c as a non-traditional chemotherapeutic, we hope to prevent metastasis by killing cancer cells before they are able to colonize metastatic sites.