AUTOCRINE TGF B AND BREAST CANCER CELL GROWTH

描述：(申请人摘要)TGFb II型受体缺失 (TGFRII)表达是ER+乳腺恶性程度的重要决定因素 通常表达受体水平不足的癌细胞。这个 申请人已显示TGFRII在MCF-7细胞中重新表达，导致 致瘤性降低。对维生素D3类似物(VD3)分离物的反应 可诱导TGFRII表达和负自分泌生长 控制力。VD3导致p21和p27细胞周期蛋白依赖水平升高 这是一种激酶抑制剂。阐明TGFRII表达的调控可能 导致增加TGFb负增长调控的关键目标，因此， VD3对治疗和/或预防的影响。第一个目标是 确定VD3类似物阻止细胞周期生长的机制。这个 申请人假设p21和p27是VD3的核心要素 生长抑制机制和TGFb活性再生导致 抑制物表达增加。缺乏TGFRII的重要性 在恶性肿瘤中的表达是理解表观遗传学的需要 在ER+细胞中抑制它的机制是第二个 目标。申请人假设并提供初步数据 抑制TGFRII与内质网功能导致DNA 甲基化。第三个目标是确定VD3类似物如何增加 TGFRII转录。具体目的是解决以下方面的问题 VD3、TGFRII的表达与细胞周期停滞的相互作用如下：1) 通过以下方法确定p21和p27 CDK抑制剂在细胞周期停滞中的作用 VD3类似物；2)测定抗雌激素治疗对TGFRII的影响 表达；3)确定甲基化抑制TGFRII的机制 4)确定VD3类似物诱导TGFRII的机制 表情。

DESCRIPTION: (Applicant's Abstract) The loss of TGFB type II receptor (TGFRII) expression is an important determinant in malignancy of ER+ breast cancer cells which generally express deficient levels of receptor. The applicant has shown re-expression of TGFRII in MCF-7 cells leading to reduced tumorigenicity. Response to vitamin D3 analogues (VD3) segregates with inducibility of TGFRII expression and negative autocrine growth control. VD3 leads to increased levels of p21 and p27 cyclin dependent kinase inhibitors. Elucidation of the controls of TGFRII expression may lead to key targets for increasing TGFB negative growth regulation and thus, VD3 effects on therapy and/or prevention. The first objective is to determine the mechanism of cell cycle growth arrest by VD3 analogues. The applicant hypothesizes that p21 and p27 are central elements in the VD3 growth arrest mechanism and that regeneration of TGFB activity leads to increased inhibitor expression. The importance of the lack of TGFRII expression in malignancy underlies the need for understanding the epigenetic mechanisms responsible for its repression in ER+ cells is the second objective. The applicant hypothesizes and provide preliminary data that repression of TGFRII is associated with ER function resulting in DNA methylation. The third objective is to determine how VD3 analogues increase TGFRII transcription. The specific aims to address these aspects of the interaction of VD3, expression of TGFRII and cell cycle arrest are to: 1) determine the role of the p21 and p27 CDK inhibitors in cell cycle arrest by VD3 analogues; 2) determine the effects of anti-estrogen treatment on TGFRII expression; 3) determine the mechanism by which methylation represses TGFRII expression; 4) determine the mechanism by which VD3 analogues induce TGFRII expression.