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

描述（由申请人提供）：Bit1对人乳腺癌细胞失巢凋亡和转化的调节乳腺癌是困扰美国和世界各地妇女的最常见的恶性肿瘤类型。这种类型的癌症的高死亡率保证了一项研究，可以确定乳腺癌细胞存活和恶性表型的关键调节剂。由于失巢凋亡抵抗是恶性转化的重要步骤，因此重建失巢凋亡敏感性可能是选择性对抗恶性细胞的治疗策略。该提案研究了Bit1（Bcl 2转录抑制剂）作为恶性乳腺细胞失巢凋亡抗性和转化的调节剂的作用。Bit1是一种线粒体蛋白，释放到胞质溶胶中，并在细胞与细胞外基质（ECM）的附着丧失后诱导半胱天冬酶非依赖性细胞凋亡。重要的是，Bit 1凋亡途径的消除不仅有助于失巢凋亡不敏感性，而且有助于肿瘤细胞的锚定独立生长能力（见初步结果）。在这方面，乳腺癌细胞很可能绕过Bit1介导的途径，以获得抗失巢凋亡和发展一个更具侵略性的恶性表型。基于公开的数据和本文所示的初步结果，本申请提出了以下假设：失巢凋亡效应子Bit1是乳腺癌细胞失巢凋亡抗性和恶性表型的负调节剂或抑制剂，并且Bit1凋亡途径的激活将刺激失巢凋亡机制并减弱与乳腺癌细胞相关的恶性表型。该提案的具体目的是：1）检查Bit1凋亡途径对乳腺癌细胞系恶性表型的调节，以及2）确定可能影响乳腺癌细胞转化的Bit1调节信号通路。这项研究的结果将为理解乳腺癌形成的分子机制提供新的信息，并强调Bit1作为乳腺癌治疗新靶点的潜力。 公共卫生相关性：Bit1对人类乳腺癌细胞失巢凋亡和转化的调节乳腺癌是困扰美国和世界各地妇女的最常见的恶性肿瘤类型。由于失巢凋亡抵抗是恶性转化的重要步骤，因此重建失巢凋亡敏感性可能是选择性对抗恶性细胞的治疗策略。该提案研究了Bit1（Bcl 2转录抑制剂）作为失巢凋亡敏感性诱导剂和乳腺癌细胞转化抑制剂的潜在治疗用途。

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.