Integrin Function in Breast Cancer Initiation

 描述(申请人提供)：乳腺癌是女性最常见的癌症诊断，也是女性癌症相关死亡的主要原因之一。起源于乳房的肿瘤由不同种类的细胞组成。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，例如能够缓慢分裂并产生分化的细胞谱系。此外，BCSCs还参与了肿瘤的发生、耐药和远处器官的转移。有了这些信息，对维持BCSCs的生物学过程的更好理解将导致针对这种对化疗和放射耐药的肿瘤细胞群体的新型药物的开发。这项拟议的工作将探索α6整合素剪接变异体α6Aβ1和α6Bβ1在白血病发生中的作用。 BCSCs，特别涉及TAZ转录辅活化子的激活机制。整合素是细胞表面受体家族，在信号转导中起作用。 以及与细胞外基质的黏附。α6Aβ1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，α6Bβ1整合素变体在BCSC中表达，并通过激活河马信号转导系统TAZ促进肿瘤启动。先前已经证明TAZ在BCSCs的功能中起重要作用，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更深入的认识 乳腺癌进展机制的研究。这项建议将使用细胞和分子生物学的方法来建立在表达非干细胞乳腺癌细胞群(目标1)的α6Aβ1中抑制TAZ的机制。还将进行生物化学研究，目的是将TAZ失活的机制与非干细胞乳腺癌细胞群体中经典的河马信号通路联系起来(目标2)。综上所述，这项建议中包含的研究将增加对BCSCs整合素调控的理解。我们的结果可以为设计未来针对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.