Cytoplasmic mislocalization of p27Kip1 as a causative factor and prognostic marke

尽管侵袭性肿瘤通常表达异常低的细胞周期抑制因子p27(P27)， 这几乎不是由于p27基因的突变造成的。尽管支持p27的重要性的数据 一个预测指标很强，它最终是我们和其他人正在定义的p27之间的关系 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实用性。它是 有时假设p27是增殖的替代物，并且它不能预测或预测超越 它在抑制细胞周期中的作用。在这个项目中，我们将建立在基本发现的基础上，确认p27功能是 更复杂的是，它的调节和细胞定位介导了肿瘤进展和细胞 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 通过评估临床结局与p27表达和细胞之间的关系的发现 乳腺癌随访至少五年的女性乳腺癌的定位 死亡率。令人信服的证据表明，p27的细胞定位可能是 对两种重要的乳腺癌治疗的反应：抗雌激素和抗HER2。要描述效果的特征 对于ANFI-雌激素和曲妥珠单抗对p27表达和定位的影响，我们将检测 这些药物给药前后的样本。这些重新启动的小型人体研究将指导 在更大的临床试验中对p27的评估，这些试验有能力评估这种蛋白的预测能力 对治疗的反应。与此同时，我们将研究一种新的途径，涉及TRIM62，这可能是 在HER2+的人乳腺癌中，p27的胞浆表达至少在一定程度上与此有关。我们 提出三个目标：目标1将检验细胞质p27是乳腺癌癌基因的假设 影响肿瘤的起始、侵袭和转移。目标2将检验这样一种假设，即通过 TRIM62是一种新的p27调控因子，在HER2依赖的致癌转化过程中起重要作用。目标3 将进一步检验细胞质p27升高是人类乳房预后标志物的假设 癌症，并询问细胞质p27是否预测对特定乳腺癌治疗的应答。

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.