Cytoplasmic mislocalization of p27Kip1 as a causative factor and prognostic marke

p27Kip1 的细胞质错误定位作为致病因素和预后标记

• 批准号: 8543565
• 负责人: PEGGY L. PORTER
• 金额: $ 22.72万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8543565
• 关键词: Address; Affect; Age; Aromatase Inhibitors; Basic Science; Biological Assay; Biopsy; Breast; Breast Cancer Cell; Breast Cancer Model; Cancer Model; Cancer cell line; Cell Cycle; Cell Cycle Regulation; Cell Nucleus; Cell Proliferation; Cells; Clinical; Clinical Trials; Cytoplasm; Data; ERBB2 gene; Enrollment; Estrogen Antagonists; Estrogen Therapy; Estrogens; Evaluation; Exhibits; Future; Genes; Goals; Human; Instruction; Malignant Neoplasms; Mammary Neoplasms; Mediating; Methods; Modeling; Monoclonal Antibodies; Mus; Mutation; Neoplasm Metastasis; Normal Cell; Nuclear; Nude Mice; Oncogenes; Oncogenic; Outcome; Pathway interactions; Patients; Phenotype; Play; Prognostic Factor; Prognostic Marker; Proteins; Recurrence; Regulation; Reporting; Resistance; Role; Sampling; Series; Testing; Translations; Trastuzumab; Woman; Xenograft procedure; base; breast tumorigenesis; cancer therapy; cell transformation; cell type; cyclin-dependent kinase inhibitor 1B; follow-up; in vitro Model; in vivo; inhibitor/antagonist; insight; interest; malignant breast neoplasm; melanoma; mortality; mouse model; neoplastic cell; novel marker; outcome forecast; overexpression; prognostic; prospective; response; tumor; tumor initiation; tumor progression

Although aggressive tumors often express abnormally low amounts of the cell cycle inhibitor p27'^'''^ (p27), this is almost never due to mutation of the p27 gene. Although the data supporting the importance of p27 as a prognosfic indicator are strong, it is ultimately the relationship that we and others are defining between p27 and response to specific breast cancer therapies that will expand the clinical ufility of this single marker. It is sometimes assumed that p27 is a surrogate for proliferation and that it is not prognostic or predictive beyond its role in inhibiting the cell cycle. In this project, we will build on basic findings that confirm p27 funcfion is more complicated and that its regulafion and cellular localization mediate tumor progression and cellular responsiveness to therapies directed at breast cancer cells. We will begin the translafion of these basic discoveries by evaluating the relationship between clinical outcome and p27 expression and cellular localization in human breast cancers of women with at least five years of follow-up for breast cancer mortality. Compelling evidence indicates that the cellular localizafion of p27 could be an indicator of response to two important breast cancer therapies: anti-estrogen and anti-HER2. To characterize the effect of an anfi-estrogen and trastuzumab on expression and localizafion of p27, we will assay protein levels in samples pre- and post-administration of these agents. These relafively small human studies will guide the evaluation of p27 in larger clinical trials that have the power to assess the ability of this protein to predict response to therapy. In parallel we will be investigating a new pathway, involving TRIM62, that may be responsible, at least in part, for the cytoplasmic expression of p27 in HER2+ human breast cancers. We propose three aims: Aim 1 will test the hypothesis that cytoplasmic p27 is a breast cancer oncogene affecting tumor initiation, invasion and metastasis. Aim 2 will test the hypothesis that regulation of p27 by TRIM62, a new p27 regulator, plays an essential role in HER2-dependent oncogenic transformation. Aim 3 will further test the hypothesis that increased cytoplasmic p27 is a prognosfic marker in human breast cancer, and ask whether cytoplasmic p27 predicts responsiveness to specific breast cancer therapeufics.

尽管侵袭性肿瘤通常表达异常低量的细胞周期抑制剂p27“^”^（p27）， 这几乎从来不是由于p27基因的突变。尽管支持p27作为 一个重要的指标是强有力的，这是最终的关系，我们和其他人正在定义之间的p27 以及对特定乳腺癌治疗的反应，这将扩大这一单一标志物的临床应用。是 有时假定p27是增殖的替代物，并且它不是预后或预测性的， 它在抑制细胞周期中的作用。在这个项目中，我们将建立在确认p27功能的基础上。 更复杂，其调节和细胞定位介导肿瘤进展和细胞凋亡。 对针对乳腺癌细胞的治疗的反应性。我们将开始对这些基本的 通过评估临床结果与p27表达和细胞凋亡之间的关系， 乳腺癌随访至少5年的女性乳腺癌定位 mortality.令人信服的证据表明，p27的细胞定位可能是一个指标， 两种重要的乳腺癌治疗：抗雌激素和抗HER2。为了描述这种效应 抗雌激素和曲妥珠单抗对p27表达和定位的影响，我们将检测 这些药物给药前和给药后的样品。这些相对较小的人类研究将指导 在较大的临床试验中评估p27，这些试验有能力评估这种蛋白质预测 对治疗反应。与此同时，我们将研究一种新的途径，涉及TRIM62，这可能是 至少部分地负责HER2+人乳腺癌中p27的细胞质表达。我们 提出三个目标：目标1：验证胞质p27是乳腺癌基因的假设 影响肿瘤的发生、侵袭和转移。目的2将检验以下假设： TRIM62是一种新的p27调节因子，在HER2依赖性致癌转化中起重要作用。目标3 将进一步检验细胞质p27增加是人类乳腺癌的一个标志物的假设 癌症，并询问细胞质p27是否预测对特定乳腺癌治疗的反应性。