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

乳腺管腔细胞和环境因素在建立 p53 缺陷癌前场中的相互作用

基本信息

批准号：
10303044
负责人：
Zhe Li
金额：
$ 36.73万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-12 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10303044
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

项目摘要

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.

癌前区域通常是指肿瘤周围组织学正常的上皮细胞，这些细胞携带一些与肿瘤中的细胞和肿瘤细胞相同的遗传和/或表观遗传变化。它们可能具有共同的克隆起源。获得细胞源后可形成癌前区域。与相邻细胞相比，克隆生长具有优势。然而，一些基因突变可以使中性竞争倾斜，从而使上皮细胞变得中性。突变细胞的“适应度”有所提高，并且有更高的机会取代它们的邻居，而其他细胞突变只能在与环境调节剂相互作用时才能做到这一点。遗传、表观遗传和环境因素的相互作用使中性克隆的随机过程倾斜竞争是了解癌前场如何形成以及如何针对 p53 的关键。突变是人类乳腺癌中最常见的突变，代表乳腺癌的早期事件通过在少数角蛋白 8+ 管腔乳腺上皮细胞中诱导 p53 丢失。 (MEC)，我们随后观察到由 p53 缺陷的管腔 MEC 组成的癌前区域；由于组成型 p53 敲除小鼠的 MEC 基本正常。表型，我们发现这种缺乏 p53 的管腔癌前场是在 p53 突变的管腔 MEC 和环境因素（例如卵巢激素、免疫细胞）。 MECs的增殖、分化和凋亡受循环卵巢激素控制，目标1将确定雌激素受体 (ER)+ 或 ER- 管腔 MEC 中诱导的 p53 缺乏是否会引发失衡 p53 突变细胞与其野生型邻居之间的增殖与凋亡的关系，导致净随着时间的推移，p53 缺陷的管腔细胞会以动情周期依赖性方式积累。进一步确定卵巢激素的周期性变化在建立p53-de发光中的作用癌前区域，通过卵巢切除术、激素（雌激素、黄体酮）替代和他莫昔芬 p53 缺陷型管腔 MEC 的表达谱揭示了独特的免疫相关特征。提示免疫抑制；我们的初步研究进一步证明 M2 极化基于这些数据，巨噬细胞可以促进管腔 MEC 的生长，Aim 3 将研究其潜力。各种免疫细胞类型，特别是巨噬细胞（例如 M2 极化）在塑造 p53- 中的作用总体而言，更好地了解激素如何相互作用。乳腺中具有 p53 突变管腔 MEC 的环境和免疫细胞有助于发育这种p53缺陷的癌前区域的研究预计将导致乳腺癌预防的新策略，特别是在高危人群（例如李法美尼综合征患者）中提出的想法和方法。这对于理解其他癌症类型的癌前区域也可能具有广泛的影响。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer.

DNA 损伤修复不充分会促进乳腺转分化，导致 BRCA1 乳腺癌。

DOI：
发表时间：
2019
期刊：
影响因子：
64.5
作者：
Wang, Hua;Xiang, Dongxi;Liu, Ben;He, Aina;Randle, Helena J;Zhang, Kelvin Xi;Dongre, Anushka;Sachs, Norman;Clark, Allison P;Tao, Luwei;Chen, Qing;Botchkarev Jr, Vladimir V;Xie, Ying;Dai, Ning;Clevers, Hans;Li, Zhe;Livingston, David M
通讯作者：
Livingston, David M

Modeling Breast Cancer via an Intraductal Injection of Cre-expressing Adenovirus into the Mouse Mammary Gland.

通过将表达 Cre 的腺病毒导管内注射到小鼠乳腺中来模拟乳腺癌。