A novel strategy targeting TP63 for breast cancer prevention

项目摘要摘要 乳腺癌是女性一生中最常见的癌症之一。具有更高级的 筛查方法中，早期乳腺癌的诊断变得越来越普遍。然而， 在理解某些早期乳腺癌进展为完全恶性的原因方面仍存在很大差距 癌症。导管原位癌(DCIS)是一种早期的乳腺非恶性病变，被认为是一种 浸润性乳腺癌(IDC)的先兆。有研究表明，中国的一小部分癌症干细胞 DCIS可能在乳腺癌的进展中起到一定作用。因此，了解癌症干细胞的作用 处于早期过渡阶段的细胞对于有效预防癌症非常重要。我们最近的研究表明，维生素D 化合物将乳腺癌细胞修饰成更少干细胞样、更分化的细胞，抑制乳房 在动物体内形成和抑制乳腺肿瘤生长。我们假设癌症干细胞起了一定的作用 在DCIS向IDC的转变中，这些小分子通过靶向关键转录因子来重新编程 癌症干细胞和减少DCIS的转变。癌症干细胞可以通过某些关键字重新编程 转录因子。一些转录因子，如Oct4，Sox-2，Klf4或其他已知的是 推动癌症干细胞的产生和维持，而肿瘤抑制基因的成员TP63 P53家族在乳腺发育和分化中起关键作用。TP63编码多个 亚型，包括TAp63和DeltaNp63两种主要形式。我们建议的研究旨在获得新的见解 肿瘤发生过程中的自我更新和分化过程，主要集中在TP63和DeltaNp63。 在目标1中，我们将使用cell检测CD44/CD24-、CD44/CD24low和CD44/CD24hi的亚群 表面标志，乳房形成和干细胞图谱，以了解平衡作用 TP63/DeltaNp63在乳腺癌中的表达乳房将是了解癌症干细胞的极好工具 体外细胞动力学和测试小分子的潜在影响。在目标2中，我们将调查 TP63和DeltaNp63在体内DCIS向IDC转化过程中的作用我们的研究旨在确定癌症预防措施 靶向TP63治疗乳腺癌的药物。小分子可以帮助将癌症干细胞重新编程为 增殖能力降低的特定细胞系可以作为乳腺癌的有用药物。 预防。癌症进展、转移和复发是乳房管理中的重大问题。 癌症。本项目可能为针对TP63的癌症预防提供一种新的策略。

Project Summary Abstract Breast cancer is one of the most common cancers affecting women in their lifetime. With more advanced screening methods, the diagnosis of early stages of breast cancer is becoming more common. However, significant gap remains in understanding why some early stage breast cancer progresses to fully malignant cancers. Ductal carcinoma in situ (DCIS) is an early, non-malignant lesion of the breast recognized as a precursor of invasive breast cancer (IDC). It is suggested that a small subpopulation of cancer stem cells in DCIS may play a role contributing to breast cancer progression. Thus, understanding the role of cancer stem cells in the early transition is important for effective cancer prevention. Our recent studies show that vitamin D compounds modify breast cancer cells to less stem-like, more differentiated cells, inhibit mammosphere formation and suppress mammary tumor growth in animals. We hypothesize that cancer stem cells play a role in DCIS transition to IDC, and these small molecules work by targeting key transcription factors to reprogram cancer stem cells and reduce DCIS transition. Cancer stem cells can be reprogrammed by certain key transcription factors. Some of transcription factors, such as Oct4, SOX-2, Klf4 or others, have been known to drive generation and maintenance of cancer stem cells, while TP63, a member of the tumor suppressor gene p53 family, plays a key role in mammary gland development and differentiation. TP63 encodes multiple isoforms, including two major forms, TAp63 and DeltaNp63. Our proposed studies aim to gain novel insights in self-renewal and differentiation process during cancer development with a key focus on TP63 and DeltaNp63. In Aim 1, we will examine the subpopulations of CD44+/CD24-, CD44+/CD24low, and CD44+/CD24hi using cell surface markers, mammosphere formation and stem cell profiles to understand the balancing role of TP63/DeltaNp63 in breast cancer. Mammospheres will be an excellent tool for understanding the cancer stem cell dynamics in vitro and testing small molecules for their potential effects. In Aim 2, we will investigate the role of TP63 and DeltaNp63 in DCIS transition to IDC in vivo. Our study aims to identify cancer preventive agents targeting TP63 in breast cancer. Small molecules that can help reprogram cancer stem cells into specific cell lineages, with reduced proliferation potential, could serve as useful agents in breast cancer prevention. Cancer progression, metastasis, and recurrence are significant problems in managing breast cancer. The present project could provide a novel strategy targeting TP63 for cancer prevention.