Interplay of mammary luminal cells and environmental factors in establishing p53-deficient premalignant field

乳腺腔细胞和环境因素在建立 p53 缺陷癌前场中的相互作用

• 批准号: 10061564
• 负责人: Zhe Li
• 金额: $ 37.48万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-12 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10061564
• 关键词: Adenoviruses; Apoptosis; Architecture; Bladder; Breast; Breast Cancer Prevention; Breast Epithelial Cells; CD4 Positive T Lymphocytes; Carcinoma; Cells; Chronic; Colon; DNA Sequence Alteration; Data; Defect; Development; Developmental Biology; Environmental Risk Factor; Epigenetic Process; Epithelial; Epithelial Cells; Esophagus; Estrogen Receptors; Estrogens; Estrous Cycle; Event; Exhibits; Expression Profiling; Gene Expression Profile; Genes; Genetic; Growth; Head and neck structure; Histologic; Hormones; Human; Immune; Immunosuppression; Incidence; Inflammation; Injections; KRASG12D; Keratin; Knockout Mice; Lead; Li-Fraumeni Syndrome; Light; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Modeling; Molecular; Mus; Mutate; Mutation; Myeloid-derived suppressor cells; Normal Cell; Organoids; Ovarian hormone; Ovariectomy; PF4 Gene; Patients; Penetrance; Periodicity; Phenotype; Physiologic pulse; Play; Progesterone; Recurrence; Risk Factors; Role; Selective Estrogen Receptor Modulators; Shapes; Stochastic Processes; Suggestion; T-Lymphocyte Subsets; TP53 gene; Tamoxifen; Testing; Time; Tissues; Ultraviolet B Radiation; base; breast tumorigenesis; cancer cell; cancer genome; cancer initiation; cancer prevention; cancer recurrence; cancer therapy; cancer type; cell type; daughter cell; fitness; genome sequencing; high risk; high risk population; in vivo; macrophage; malignant breast neoplasm; mammary; mammary epithelium; mouse genetics; mouse model; mutant; neoplastic cell; novel; novel strategies; precursor cell; premalignant; promoter; self-renewal; stem; stem cell biology; stem cells; tissue stem cells; tool; tumor; tumor-immune system interactions

Premalignant field often refers to histologically normal epithelial cells surrounding a tumor that carry some of the same genetic and/or epigenetic changes as in the tumor. Such cells and tumor cells surrounded by them may have a common clonal origin. A premalignant field can be formed upon its cell-of-origin acquiring a clonal growth advantage over its neighbor cells. Normally clonal competition between equipotent epithelial cells is neutral. However, some genetic mutations can tilt the neutral competition so that the mutated cells have increased “fitness” and a higher chance to replace their neighbors, whereas other mutations can only do so upon interaction with environmental modifiers. A better understanding of how the interplay of genetic, epigenetic and environmental factors tilts the stochastic process of neutral clonal competition is the key for understanding how premalignant field is formed and how it can be targeted. p53 mutation is the most common mutation in human breast cancer and represents an early event in breast tumorigenesis. By inducing p53-loss in a small number of Keratin 8+ luminal mammary epithelial cells (MECs), we observed a premalignant field comprised of p53-deficient luminal MECs; mammary tumors later emerged from it with 100% penetrance. Since constitutive p53 knockout mice have a largely normal MEC phenotype, we hypothesize that this p53-deficient luminal premalignant field is formed upon interplay of p53-mutant luminal MECs and environmental factors (e.g., ovarian hormones, immune cells). As proliferation, differentiation and apoptosis of MECs are controlled by cyclic ovarian hormones, Aim 1 will determine if induced p53-deficiency in estrogen receptor (ER)+ or ER- luminal MECs triggers an imbalance of proliferation versus apoptosis between p53 mutant cells and their wild-type neighbors, resulting in a net accumulation of p53-deficent luminal cells over time, in an estrous cycle-dependent manner. Aim 2 will further determine the role of cyclic changes of ovarian hormones in establishing the p53-deficient luminal premalignant field, by ovariectomy, hormone (estrogen, progesterone) replacement, and tamoxifen treatment. Expression profiling of p53-deficient luminal MECs revealed a unique immune-related signature suggestive of immunosuppression; our preliminary study further demonstrated that M2-polarized macrophages could enhance growth of luminal MECs. Based on these data, Aim 3 will investigate potential roles of various immune cell types, in particular, macrophages (e.g., M2-polarized), in shaping the p53- deficient luminal premalignant field. Overall, a better understanding of how interaction of the hormone milieu and immune cells in the mammary gland with p53-mutant luminal MECs contributes to development of this p53-deficient premalignant field is expected to lead to novel strategies of breast cancer prevention, particular in high-risk populations (e.g., Li-Fraumeni syndrome patients). The idea and approach proposed here may also have broad-reaching implications in understanding premalignant fields in other cancer types.

前态场通常是指围绕肿瘤的组织学正常上皮细胞，该细胞携带一些 与肿瘤中相同的遗传和/或表观遗传学变化。这些细胞和肿瘤细胞周围 他们可能具有共同的克隆起源。可以在其原始细胞中形成预启示性场 克隆生长优势比其邻居细胞。通常在等值之间的克隆竞争 上皮细胞是中性的。但是，某些遗传突变可以倾斜中立竞争，以便 突变的细胞增加了“适合度”，更换邻居的机会更高，而其他 突变只能在与环境修饰符相互作用后才这样做。更好地理解如何 遗传，表观遗传和环境因素的相互作用倾斜了中性克隆的随机过程 竞争是了解如何形成预示威的关键以及如何将其定向。 p53 突变是人类乳腺癌中最常见的突变，代表了乳房的早期事件 肿瘤发生。在少数角蛋白8+腔乳腺上皮细胞中诱导的p53损失 （MEC），我们观察到p53缺乏腔内的MEC的预立场完成；乳腺肿瘤后来 从中出现了100％的渗透率。由于本构p53敲除小鼠的MEC主要正常 表型，我们假设该p53缺陷的腔内前磁场是在相互作用时形成的 p53突出的腔内MEC和环境因素（例如，卵巢激素，免疫细胞）。作为 MEC的增殖，分化和凋亡受环状卵巢激素控制，AIM 1将 确定雌激素受体（ER）+或ER-Luminal Mecs中诱导的p53缺陷是否会触发不平衡 p53突变细胞与其野生型邻居之间的增殖与凋亡 随着时间的流逝，p53剂量细胞的积累，以发情循环依赖性方式积聚。 AIM 2意志 进一步确定卵巢骑兵在建立p53缺陷腔中的循环变化的作用 卵形切除术，马酮（雌激素，孕激素）替代品和他莫昔芬 治疗。 p53缺陷腔腔MEC的表达分析显示出独特的免疫相关特征 暗示免疫抑制；我们的初步研究进一步证明了M2偏振 巨噬细胞可以增强腔内MEC的生长。基于这些数据，AIM 3将研究潜力 尤其是巨噬细胞（例如M2偏振）的各种免疫力类型的作用，在塑造p53-- 不足的腔内前域。总体而言，更好地了解马的相互作用 用p53突变的腔腔MEC在乳腺中的环境和免疫细胞有助于发展 预计该p53缺陷前效率将导致预防乳腺癌的新策略， 特别是在高危人群中（例如Li-Fraumeni综合征患者）。提出的想法和方法 这里可能对了解其他癌症类型的前态度领域具有广泛的含义。