CAV-1, Stat5a Signaling, and Estrogen-Dependent Breast Cancer

CAV-1、Stat5a 信号传导和雌激素依赖性乳腺癌

• 批准号: 8206585
• 负责人: Philippe G. Frank
• 金额: $ 32.57万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-23 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206585
• 关键词: Behavior; Breast Cancer Cell; CAV1 gene; Cancer Patient; Cells; Cyclin D1; Cyclins; Dominant-Negative Mutation; Estrogen Receptor alpha; Estrogen Receptors; Estrogen receptor negative; Estrogen receptor positive; Estrogens; Gene Silencing; Human; Hyperplasia; Knock-out; Knockout Mice; Lung; Mammary Tumorigenesis; Mammary gland; Mus; Mutation; Neoplasm Metastasis; Ovariectomy; Pathogenesis; Patients; Phosphotransferases; Primary Neoplasm; Prognostic Marker; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Small Interfering RNA; Supplementation; Tamoxifen; Transplantation; Tumor Suppressor Proteins; Up-Regulation; caveolin 1; inhibitor/antagonist; malignant breast neoplasm; mammary epithelium; meetings; novel

CAV-1, StatSa Signaling, and Estrogen-Dependent Breast Cancer The human Caveolin-1 (Cav-1) gene acts as a mammary gland tumor suppressor. We have previously identified Cav-1 inactivating (dominant-negative (DN)) mutations in up to 35 % of estrogen receptor (ER) positive breast cancer patients. Our hypothesis is that up-regulation of ER levels and activity are caused by Cav-1 inactivating mutations. As Cav-1 functions as an inhibitor of the Jak-2 kinase, we propose that StatSa activation is the mechanism by which loss of Cav-1 function results in increased ER-alpha levels. In support of this hypothesis, we present novel evidence that StatSa activation is sufficient to upregulate ER-alpha levels in ER-negative human breast cancer cells. As such, our preliminary studies have now defined a novel signaling pathway leading to breast cancer: Cav-1 gene inactivation (DN-mutations) --> StatSa activation --> ER-alpha upreoulation -> Cvclin D1 over-expression. The three Specific Aims of the project are: 1) Determine the role of StatSa activation and ER-alpha in Cav-1-related mammary hyperplasia. proliferation, and 3D lumen formation. We will analyze the mammary glands of Cav-1/StatSa double- knockout mice and study the ex vivo behavior of primary cultures of mammary epithelia from these mice. 2) Determine the role of StatSa activation and ER-alpha in Cav-1-related mammary tumorigenesis and metastasis. For this purpose, we will perform orthotopic transplantation of Met-1 cells expressing Cav-1 dominant-negative (DN) mutants (such as P132L) that are found in human breast cancer. The role of StatSa signaling will be assessed using DN mutants of StatSa and Jak-2. The role of estrogen will be assessed by ovariectomy and supplementation with estrogen pellets. Tamoxifen-resistance will also be investigated. 3) Determine if Cav-1 mutations co-segregate with StatSa activation in ER(+) human breast cancer samples. Here, we propose to examine the relevance of this newly defined signaling pathway in human breast cancer pathogenesis, using Cav-1 mutations, ER-alpha expression levels, and StatSa activation as novel prognostic markers. Since greater than 40% of ER-apha positive patients show tamoxifen-resistance, we will also examine if Cav-1 mutations and StatSa activation are critical predictors of tamoxifen-resistance.

CAV-1、StatSa信号转导与雌激素依赖性乳腺癌 人Caveolin-1（Cav-1）基因是一种乳腺肿瘤抑制基因。我们先前已经 在高达35%的雌激素受体（ER）中发现Cav-1失活（显性阴性（DN））突变 乳腺癌患者。我们的假设是，ER水平和活性的上调是由以下因素引起的： Cav-1失活突变。由于Cav-1作为Jak-2激酶的抑制剂发挥作用，我们建议StatSa 激活是Cav-1功能丧失导致ER-α水平升高的机制。支持 根据这一假设，我们提出了新的证据，即StatSa激活足以上调ER-α ER阴性人乳腺癌细胞中的水平。因此，我们的初步研究已经确定了一部小说 导致乳腺癌的信号通路：Cav-1基因失活（DN突变）--> StatSa激活--> ER-α上调-> Cvclin D1过表达。该项目的三个具体目标是： 1)确定StatSa激活和ER-α在Cav-1相关乳腺增生中的作用。 增殖和3D管腔形成。我们将分析Cav-1/StatSa双- 敲除小鼠，并研究来自这些小鼠的乳腺上皮原代培养物的离体行为。 2)确定StatSa激活和ER-α在Cav-1相关乳腺肿瘤发生中的作用， 转移为此，我们将进行表达Cav-1的Met-1细胞的原位移植 在人类乳腺癌中发现的显性阴性（DN）突变体（如P132 L）。Stata的作用 使用StatSa和Jak-2的DN突变体评估信号传导。雌激素的作用将通过 卵巢切除术和补充雌激素丸。还将研究他莫昔芬耐药性。 3)确定ER（+）人乳腺癌中Cav-1突变是否与StatSa激活共分离 样品在这里，我们建议研究这个新定义的信号通路在人类中的相关性。 乳腺癌发病机制，使用Cav-1突变，ER-α表达水平和StatSa激活作为 新的预后标志物。由于超过40%的ER-apha阳性患者显示出他莫昔芬耐药性， 我们还将研究Cav-1突变和StatSa激活是否是他莫昔芬耐药的关键预测因子。

项目成果

Scavenger receptor class B type I regulates cellular cholesterol metabolism and cell signaling associated with breast cancer development.

• DOI: 10.1186/bcr3483
• 发表时间: 2013
• 期刊: Breast cancer research : BCR
• 作者: Danilo C;Gutierrez-Pajares JL;Mainieri MA;Mercier I;Lisanti MP;Frank PG
• 通讯作者: Frank PG

Caveolin-1 tumor-promoting role in human melanoma.

• DOI: 10.1002/ijc.24451
• 发表时间: 2009-10-01
• 期刊: International journal of cancer
• 影响因子: 6.4
• 作者: Felicetti F;Parolini I;Bottero L;Fecchi K;Errico MC;Raggi C;Biffoni M;Spadaro F;Lisanti MP;Sargiacomo M;Carè A
• 通讯作者: Carè A