Regulation of anoikis and transformation in human breast cancer cells by Bit1

Bit1 对人乳腺癌细胞失巢凋亡和转化的调节

基本信息

批准号：
8061665
负责人：
Hector Ramos Biliran
金额：
$ 10.86万
依托单位：
XAVIER UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8061665
关键词：
Anchorage-Independent Growth Anoikis Apoptosis Apoptotic Attenuated Biology Breast Breast Cancer Cell Breast Carcinoma Bypass Cancer Biology Cancer Center Caspase Cell Line Cell Survival Cell-Matrix Junction Cells Cytosol Data Development Epithelial Cells Exhibits Extracellular Matrix Funding Future Genetic Transcription Goals Guidelines Historically Black Colleges and Universities Human Human Resources Institutes Integrin-mediated Cell Adhesion Pathway Integrins Journals Knowledge Louisiana Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mediating Medical Research Mitochondrial Proteins Molecular Oncogenes PI3K/AKT Pathway interactions Peer Review Phosphorylation Phosphotransferases Pilot Projects Principal Investigator Property Proteins Proto-Oncogene Proteins c-akt Publishing Regulation Research Resistance Resistance development Role Scientist Signal Pathway Signal Transduction Students Testing Therapeutic Therapeutic Uses Time Tumorigenicity United States Universities Woman Work base cancer cell cancer therapy cancer type cell transformation combat effective therapy extracellular inhibitor/antagonist malignant breast neoplasm malignant phenotype mortality neoplastic cell novel professor programs protein kinase D public health relevance tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Regulation of anoikis and transformation in human breast cancer cells by Bit1 Breast cancer is the most common type of malignancy afflicting women in the United States and around the world. The high mortality rate in this type of cancer warrants a study that can identify key modulators of breast cancer cell survival and malignant phenotype. Since anoikis resistance is an essential step in malignant transformation, re-establishing anoikis sensitivity may be a therapeutic strategy in selectively combating malignant cells. This proposal examines the role of Bit1 (Bcl2 inhibitor of transcription) as a regulator of anoikis resistance and transformation in malignant breast cells. Bit1 is a mitochondrial protein that is released to the cytosol and induces a caspase-independent apoptosis following loss of cell attachment to the extracellular matrix (ECM). Importantly, abrogation of the Bit1 apoptosis pathway contributes not only in anoikis insensitivity but also in the anchorage independent growth capacity of tumor cells (see preliminary results). In this regard, mammary carcinoma cells are likely to bypass the Bit1-mediated pathway to attain anoikis resistance and develop a more aggressive malignant phenotype. Based on published data and preliminary results shown herein, this application proposes the following hypothesis: the anoikis effector Bit1 is a negative regulator or a suppressor of anoikis resistance and malignant phenotype of breast cancer cells, and that activation of Bit1 apoptosis pathway will stimulate anoikis mechanism and attenuate the malignant phenotype associated with breast cancer cells. The specific aims of this proposal are: 1) to examine the regulation of the malignant phenotype of breast carcinoma cell lines by the Bit1 apoptosis pathway, and 2) to determine the Bit1-regulated signaling pathways that may impact breast cancer cell transformation. The results of this study will provide new information in understanding the molecular mechanisms underlying breast cancer formation and underscore the potential of Bit1 as a novel target in breast cancer therapy. PUBLIC HEALTH RELEVANCE: Regulation of anoikis and transformation in human breast cancer cells by Bit1 Breast cancer is the most common type of malignancy afflicting women in the United States and around the world. Since anoikis resistance is an essential step in malignant transformation, re-establishing anoikis sensitivity may be a therapeutic strategy in selectively combating malignant cells. This proposal examines the potential therapeutic use of Bit1 (Bcl2 inhibitor of transcription) as an inducer of anoikis sensitivity and an inhibitor of transformation in breast cancer cells.

描述（由申请人提供）：BIT1乳腺癌对人类乳腺癌细胞中厌氧菌的调节是最常见的恶性肿瘤类型。这种类型的癌症的高死亡率需要一项研究，该研究可以鉴定乳腺癌细胞存活和恶性表型的关键调节剂。由于Anoikis耐药性是恶性转化的重要步骤，因此重新建立Anoikis敏感性可能是选择性地对抗恶性细胞的治疗策略。该提案研究了BIT1（转录的BCL2抑制剂）作为恶性乳腺细胞中厌食和转化的调节剂的作用。 BIT1是一种线粒体蛋白，在细胞外基质（ECM）失去细胞附着后，释放到细胞质蛋白并诱导caspase非依赖性凋亡。重要的是，BIT1凋亡途径的废除不仅在Anoikis不敏感性中贡献，而且在肿瘤细胞的锚固独立生长能力中也有贡献（请参阅初步结果）。在这方面，乳腺癌细胞可能会绕过Bit1介导的途径，以达到厌氧抗性并发展出更具侵略性的恶性表型。基于本文所示的已发布数据和初步结果，该应用提出了以下假设：Anoikis效应子Bit1是负调节剂或抑制Anoikis抗药性和乳腺癌细胞的恶性表型的抑制剂，Bit1凋亡途径的激活将刺激Anoikis机制机制和术语与术中的恶性癌细胞相关。该提案的具体目的是：1）检查通过BIT1凋亡途径对乳腺癌细胞系的恶性表型的调节，以及2）确定可能影响乳腺癌细胞转化的位1.位调节的信号通路。这项研究的结果将提供新的信息，以了解乳腺癌形成的分子机制，并强调Bit1作为乳腺癌治疗中的新靶标的潜力。公共卫生相关性：BIT1乳腺癌对人类乳腺癌细胞中厌氧菌的调节和转化是美国及世界各地最常见的恶性肿瘤类型。由于Anoikis耐药性是恶性转化的重要步骤，因此重新建立Anoikis敏感性可能是选择性地对抗恶性细胞的治疗策略。该提案研究了BIT1（转录的BCL2抑制剂）作为Anoikis敏感性的诱导剂的潜在治疗用途和乳腺癌细胞转化的抑制剂。