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

描述（由申请人提供）：Bit1对人乳腺癌细胞凋亡和转化的调控乳腺癌是美国和世界各地女性最常见的恶性肿瘤。这种类型癌症的高死亡率值得进行研究，以确定乳腺癌细胞存活和恶性表型的关键调节因子。由于anoikis耐药性是恶性转化的必要步骤，重建anoikis敏感性可能是一种选择性对抗恶性细胞的治疗策略。本研究探讨了Bit1 （Bcl2转录抑制剂）在恶性乳腺细胞中作为anoikis抗性和转化调节因子的作用。Bit1是一种线粒体蛋白，它被释放到细胞质中，在细胞失去与细胞外基质（ECM）的附着后诱导caspase非依赖性凋亡。重要的是，Bit1凋亡通路的缺失不仅会导致anoikis不敏感，还会影响肿瘤细胞的锚定独立生长能力（见初步结果）。在这方面，乳腺癌细胞可能绕过bit1介导的途径获得anoikis抗性，并发展出更具侵略性的恶性表型。基于已发表的数据和本文所显示的初步结果，本申请提出以下假设：anoikis效应物Bit1是乳腺癌细胞anoikis耐药和恶性表型的负调节因子或抑制因子，激活Bit1凋亡通路将刺激anoikis机制，减轻乳腺癌细胞相关的恶性表型。本课题的具体目的是：1)研究Bit1凋亡通路对乳腺癌细胞系恶性表型的调控；2)确定Bit1调控的可能影响乳腺癌细胞转化的信号通路。该研究结果将为了解乳腺癌形成的分子机制提供新的信息，并强调Bit1作为乳腺癌治疗的新靶点的潜力。

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.