Stem-like Cancer Cells in Breast Tumorigenesis

描述(申请人提供)：我的研究的长期目标是揭示癌症干细胞的本质，并设计能够针对这些细胞治疗乳腺癌的治疗方法。本应用的目的是建立NS和Ngp1在乳腺癌细胞中的表达模式，确定表达NS和Ngp1的细胞的生长表型和基因表达谱，为阐明NS细胞在乳腺肿瘤发生中的作用提供实验依据。中心假说是，NS和Ngp1在乳腺肿瘤中优先由干细胞样细胞表达，这些细胞与乳腺癌的快速生长、耐药和高转移有关。其基本原理是，癌症干细胞与体细胞干细胞共享共同的分子，如NS和Ngp1，以驱动自我更新机制。癌症干细胞负责恶性乳腺癌的高生长速度和耐药性。因此，清除表达NS的乳腺癌细胞将抑制肿瘤的发生和发展。为了实现这项提案的总体目标，将追求三个具体目标。第一个目的是建立NS和Ngp1在正常乳腺组织和乳腺癌细胞中的表达模式。第二个目的是通过用活的有色蛋白对这些细胞进行基因标记，并用流式细胞仪纯化它们，来确定这些表达NS和Ngp1的细胞的细胞和分子特性。第三个目标是通过评估NS细胞消除的后果来确定NS细胞在乳腺肿瘤的发展、进展和复发中的作用。一种可诱导的细胞消融系统将被用于在转基因动物中靶向NS细胞。这些结果将为在癌症治疗中使用干细胞靶向治疗提供亟需的理由，并为开发新的药物和基因疗法提供有价值的信息，这些药物和基因疗法可以特异性地靶向这些癌症干细胞，以治愈晚期乳腺癌。

DESCRIPTION (provided by applicant): The long-range goal of my research is to uncover the nature of the cancer stem cells, and to design therapeutic approaches that can specifically target these cells for the treatment of breast cancers. The objective of this application is to establish the expression pattern of NS and Ngp1 in breast cancer cells, determine the growth phenotype and gene expression profile of NS- and Ngp1-expressing cells, and provide experimental evidence that demonstrates the role of NS+ cells in breast tumorigenesis. The central hypothesis is that NS and Ngp1 are preferentially expressed by the stem-like cells in breast tumors, and that these cells are responsible for the rapid growth, drug resistance, and high metastasis of malignant breast cancers. The rationale is that cancer stem cells, which are responsible for the high growth rate and drug resistance of malignant breast cancers, share common molecules such as NS and Ngp1 with somatic stem cells to drive the self-renewing machinery. Therefore, eliminating NS-expressing breast cancer cells will inhibit tumor initiation and progression. To accomplish the overall objective of this proposal, three specific aims will be pursued. The first aim is to establish the expression pattern of NS and Ngp1 in normal breast tissues and breast cancer cells. The second aim is to determine the cellular and molecular properties of those NS- and Ngp1-expressing cells by genetically marking these cells with living color proteins and purifying them by flow cytometry. The third aim is to determine the role of NS+ cells in the development, progression, and recurrence of breast tumors by evaluating the consequences of their elimination. An inducible cell ablation system will be employed to target the NS+ cells in transgenic animals. These results will provide the much-needed justification for the use of stem cell-targeting therapy in cancer treatment, and valuable information for developing new pharmacological and genetic therapies that can specifically target these cancer stem cells in order to cure advanced breast carcinomas.