A novel strategy targeting TP63 for breast cancer prevention

一种针对 TP63 预防乳腺癌的新策略

• 批准号: 10608150
• 负责人: Nanjoo Suh
• 金额: $ 7.85万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-11 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608150
• 关键词: Affect; Animals; Binding; Biological Assay; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer Prevention; CD44 gene; Cell Differentiation process; Cell Lineage; Cell surface; Cells; Characteristics; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Differentiation Inducer; Early Diagnosis; Engineering; Epithelium; Estrogen receptor positive; Family; Generations; Goals; Human; Immunodeficient Mouse; In Situ Lesion; In Vitro; Intervention; Invasive Lesion; Knock-out; Laboratories; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mammospheres; Methods; Modeling; Mutation; Neoplasm Metastasis; New Agents; Non-Malignant; Noninfiltrating Intraductal Carcinoma; Oncogenes; Play; Prevention approach; Prevention strategy; Preventive; Process; Protein Isoforms; Recurrence; Role; System; TP53 gene; Testing; Tissues; Transactivation; Tumor Suppressor Genes; Vitamin D; Woman; Work; aldehyde dehydrogenases; breast cancer progression; breast lesion; cancer complication; cancer prevention; cancer stem cell; drug candidate; epithelial stem cell; genetic approach; in vivo; insight; malignant breast neoplasm; mammary gland development; member; mouse model; novel; novel strategies; novel therapeutics; overexpression; premalignant; prognosis biomarker; programs; proliferation potential; screening; self-renewal; small molecule; small molecule inhibitor; stem; stem cell biomarkers; stem cells; targeted agent; tool; transcription factor; treatment strategy; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

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.

项目摘要 乳腺癌是影响妇女一生的最常见癌症之一。与更先进 乳腺癌的早期诊断是乳腺癌的早期诊断。然而，在这方面， 在理解为什么一些早期乳腺癌发展为完全恶性方面仍然存在重大差距 癌的导管原位癌（DCIS）是一种早期的非恶性乳腺病变， 浸润性乳腺癌（IDC）的前兆。这表明，一个小的癌症干细胞亚群， DCIS可能在乳腺癌进展中发挥作用。因此，了解癌症干细胞的作用 早期转化的细胞对于有效的癌症预防是重要的。我们最近的研究表明维生素D 化合物将乳腺癌细胞修饰为更少的干细胞样，更分化的细胞， 形成并抑制动物乳腺肿瘤生长。我们假设癌症干细胞 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编程 癌症干细胞和减少DCIS转变。癌症干细胞可以通过某些关键重新编程 转录因子已知一些转录因子，如Oct 4、SOX-2、Klf 4等， 驱动癌症干细胞的产生和维持，而TP 63，肿瘤抑制基因的成员， p53家族在乳腺发育和分化中起关键作用。TP 63编码多个 同种型，包括两种主要形式，TAp 63和DeltaNp 63。我们提出的研究旨在获得新的见解， 癌症发展过程中的自我更新和分化过程，重点关注TP 63和DeltaNp 63。 在目的1中，我们将使用细胞技术检测CD 44 +/CD 24-、CD 44 +/CD 24 low和CD 44 +/CD 24 hi亚群， 表面标志物，乳腺球形成和干细胞概况，以了解平衡作用， TP 63/DeltaNp 63在乳腺癌中的作用乳腺微球将成为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作用。在目标2中，我们将研究 TP 63和DeltaNp 63在体内DCIS向IDC转变中的作用。我们的研究旨在确定癌症预防 乳腺癌中靶向TP 63的药物。小分子可以帮助癌症干细胞重新编程为 具有降低的增殖潜力的特定细胞系可以作为乳腺癌的有用试剂 预防癌症进展、转移和复发是乳腺癌治疗中的重要问题 癌本项目可能为预防癌症提供一种新的靶向TP 63的策略。