AUTOCRINE TGF B AND BREAST CANCER CELL GROWTH

描述：（申请人的摘要）TGFB II型受体的丧失 TGFRII表达是ER+乳腺癌恶性的重要决定因素 通常表达缺陷水平的受体的癌细胞。 的 申请人已经显示TGFRII在MCF-7细胞中的再表达导致 降低致瘤性。 对维生素D3类似物（VD 3）的反应分离 诱导TGFRII表达和负自分泌生长 控制 VD 3导致p21和p27细胞周期蛋白依赖性水平增加 激酶抑制剂。 阐明TGFRII表达的控制可能 导致增加TGFB负生长调节的关键目标， VD 3对治疗和/或预防的影响。 第一个目标是 确定VD 3类似物对细胞周期生长阻滞的机制。 的 申请人假设p21和p27是VD 3中的中心元件 生长停滞机制和TGFB活性再生导致 抑制剂表达增加。 缺乏TGFRII的重要性 恶性肿瘤中的表达是理解表观遗传 负责ER+细胞中其抑制的机制是第二种 objective. 申请人假设并提供初步数据， TGFRII的抑制与ER功能相关，导致DNA 甲基化 第三个目标是确定VD 3类似物如何增加 TGFRII转录。 解决这些问题的具体目标是： VD 3、TGFRII表达和细胞周期阻滞相互作用是：1） 确定p21和p27 CDK抑制剂在细胞周期阻滞中的作用， VD 3类似物; 2）确定抗雌激素治疗对TGFRII的影响 3）确定甲基化抑制TGFRII的机制 4）确定VD 3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.