Integrin Function in Breast Cancer Initiation

整合素在乳腺癌发生中的功能

• 批准号: 9918262
• 负责人: Ameer Elaimy
• 金额: $ 3.02万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-03 至 2022-05-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918262
• 关键词: Actins; Address; Adhesions; Alternative Splicing; Area; Behavior; Binding; Binding Sites; Biochemical; Biologic Characteristic; Biological Markers; Biological Process; Breast; Breast Cancer Cell; Breast Cancer Patient; Cancer Etiology; Cell Surface Receptors; Cell physiology; Cells; Collagen; Cytoplasmic Tail; Cytoskeleton; Data; Development; Disease; Distant; Down-Regulation; Environment; Epithelial; Epithelium; Extracellular Matrix; Family; Future; Goals; Integrin alpha Chains; Integrin alpha6; Integrin alpha6beta1; Integrins; Laboratories; Laminin; MAP4K4 gene; MAPK8 gene; Mammary gland; Mass Spectrum Analysis; Mediating; Mitogen-Activated Protein Kinases; Molecular and Cellular Biology; Mus; Neoplasm Metastasis; Normal tissue morphology; Organ; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Play; Population; Population Heterogeneity; Property; Protein Isoforms; RNA Splicing; Radio; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Transcription Coactivator; Transducers; Tumor Biology; Tumor Subtype; Tumor Suppressor Proteins; Variant; Woman; Work; breast cancer progression; cancer cell; cancer diagnosis; cancer initiation; cancer stem cell; conventional therapy; design; effective therapy; extracellular; improved; insight; malignant breast neoplasm; mammary epithelium; molecular targeted therapies; mortality; neoplastic cell; novel; public health relevance; receptor binding; receptor function; stem; stem cell population; stem cells; targeted treatment; therapy resistant; tissue stem cells; tumor; tumor initiation; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): Breast cancer is the most common cancer diagnosis in women and is also one of the leading causes of cancer-related mortality in women who suffer from this condition. Tumors that originate in the breast consist of heterogeneous populations of cells. Breast cancer stem cells (BSCSs) are a subtype of tumor cells that have properties similar to normal, tissue stem cells such as the ability to divide slowly and give rise to differentiated cellular lineages. Furthermore, BCSCs have been implicated in tumor initiation, therapy resistance and metastasis to distant organs. Given this information, a greater understanding of the biological processes that sustain BCSCs will lead to the development of novel agents directed against this chemo- and radio-resistant population of tumor cells. The proposed work will explore the role of the α6 integrin splicing variants, α6Aβ1 and α6Bβ1, in the genesis of BCSCs, specifically addressing the mechanism of activation of the TAZ transcriptional coactivator. Integrins are a family of cell surface receptors that function in signal transduction and adhesion to the extracellular matrix. The α6Aβ1 integrin variant is expressed in differentiated, epithelial breast cancer cells and inhibits the acquisition of stem cell properties Conversely, the α6Bβ1 integrin variant is expressed in BCSCs and promotes tumor initiation by activating the Hippo signaling pathway transducer TAZ. TAZ has previously been shown to be important in the functioning of BCSCs, but the mechanism is unknown. Therefore, elucidating the relationship between the α6 integrin splicing variants and TAZ activation will provide insight into mechanisms of breast cancer progression. This proposal will use a cellular and molecular biology approach to establish the mechanism by which TAZ is suppressed in the α6Aβ1 expressing non-stem breast cancer cell population (Aim 1). Biochemical studies will also be undertaken with the purpose of connecting mechanisms of TAZ inactivation with classical Hippo pathway signaling in the non-stem breast cancer cell population (Aim 2). In summary, the studies included in this proposal will increase the understanding of integrin regulation of BCSCs. Our results can provide rationale in designing future targeted therapies for treatment resistant subtypes of breast cancer.

 描述（由适用提供）：乳腺癌是女性最常见的癌症诊断，也是患有这种疾病的女性中与癌症相关死亡率的主要原因之一。起源于乳房的肿瘤由细胞的异质种群组成。乳腺癌干细胞（BSCS）是具有类似于正常组织干细胞的特性的肿瘤细胞的亚型，例如缓慢分裂并引起分化的细胞谱系的能力。此外，BCSC已在肿瘤起始，耐药性和远处器官的转移中实施。鉴于此信息，对维持BCSC的生物学过程有更深入的了解将导致针对这种抗化学和放射性肿瘤细胞种群的新型药物的发展。提出的工作将探讨α6整合素剪接变体α6Aβ1和α6Bβ1的作用， BCSC，专门针对TAZ转录共激活因子的激活机理。整联蛋白是一个在信号转导中起作用的细胞表面受体家族 并遵守细胞外基质。 α6Aβ1整联蛋白变体在分化的上皮乳腺癌细胞中表达，并抑制干细胞特性的获取，相反，α6Bβ1整合素变体在BCSC中表达，并通过激活Hippo信号传输途径TAZ来促进肿瘤起始。先前已证明TAZ在BCSC的功能中很重要，但是该机制尚不清楚。因此，阐明α6整合素剪接变体与TAZ激活之间的关系将提供洞察力 进入乳腺癌进展的机制。该建议将使用细胞和分子生物学方法来建立在表达非茎乳腺癌细胞群体中抑制TAZ的机制（AIM 1）。还将进行生化研究，目的是将TAZ失活的机制与非茎乳腺癌细胞种群中的经典河马途径信号传导联系起来（AIM 2）。总而言之，该提案中包括的研究将增加对BCSC整合素调节的理解。我们的结果可以为设计未来的靶向治疗乳腺癌亚型靶向疗法提供理由。