Integrin Function in Breast Cancer Initiation

 描述（由申请人提供）：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癌症相关死亡率的主要原因之一。起源于乳腺的肿瘤由异质细胞群组成。乳腺癌干细胞（BSCS）是肿瘤细胞的一种亚型，具有与正常组织干细胞相似的特性，例如缓慢分裂并产生分化细胞谱系的能力。此外，BCSC已经涉及肿瘤起始、治疗抗性和向远端器官的转移。鉴于这一信息，对维持BCSC的生物学过程的更深入理解将导致开发针对这种耐化学和放射性肿瘤细胞群体的新型药物。这项工作将探讨α6整合素剪接变体α 6 A β1和α 6 B β1在肿瘤发生中的作用。 BCSC，特别是TAZ转录共激活因子的激活机制。 整合素是一类在信号转导中起作用的细胞表面受体 以及与细胞外基质的粘附。α 6 A β1整合素变体在分化的上皮性乳腺癌细胞中表达，并抑制干细胞特性的获得。相反，α 6 B β1整合素变体在BCSC中表达，并通过激活Hippo信号通路转导物TAZ促进肿瘤起始。TAZ先前已被证明在BCSC的功能中很重要，但其机制尚不清楚。因此，阐明α6整合素剪接变异体与TAZ激活之间的关系将提供深入了解 乳腺癌进展的机制。该提案将使用细胞和分子生物学方法来建立TAZ在表达α 6 A β1的非干乳腺癌细胞群中被抑制的机制（Aim 1）。还将进行生物化学研究，目的是将TAZ失活机制与非干细胞乳腺癌细胞群中的经典Hippo通路信号传导联系起来（目的2）。 总之，本提案中包含的研究将增加对BCSC整合素调控的理解。我们的研究结果可以为设计未来的乳腺癌耐药亚型的靶向治疗提供理论依据。

 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.