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

癌前区通常是指肿瘤周围组织学上正常的上皮细胞， 与肿瘤中相同的遗传和/或表观遗传变化。这些细胞和肿瘤细胞被 它们可能具有共同的克隆起源。癌前区可在其原始细胞获得 相对于其邻近细胞的克隆生长优势。正常情况下， 上皮细胞呈中性。然而，一些基因突变可以使中性竞争倾斜， 突变的细胞增加了“适应性”，并且有更高的机会取代它们的邻居，而其他细胞则没有。 突变只有在与环境修饰剂相互作用时才能这样做。更好地理解 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发生倾斜， 竞争是理解癌前区如何形成和如何靶向的关键。p53 突变是人类乳腺癌中最常见的突变， 肿瘤发生通过在少量角蛋白8+管腔乳腺上皮细胞中诱导p53丢失， （MEC），我们观察到一个癌前区组成的p53缺陷管腔MEC;乳腺肿瘤后， 以百分之百的清醒状态出现由于组成型p53基因敲除小鼠具有基本正常的MEC， 表型，我们假设这种p53缺陷的管腔癌前区是在以下因素的相互作用下形成的： p53突变型管腔MEC和环境因素（例如，卵巢激素、免疫细胞）。作为 MECs的增殖、分化和凋亡受卵巢周期性激素的调控，Aim 1将调节MECs的增殖、分化和凋亡， 确定雌激素受体（ER）+或ER-管腔MEC中诱导的p53缺陷是否会引发失衡 p53突变细胞和它们的野生型邻居之间的增殖与凋亡的关系， 随着时间的推移，p53缺陷的管腔细胞以发情周期依赖的方式积累。目标2将 进一步确定卵巢激素的周期性变化在建立p53缺陷型管腔型卵巢癌中的作用。 癌前病变，通过卵巢切除术、激素（雌激素、孕激素）替代和他莫昔芬 治疗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表明，M2极化 巨噬细胞可促进管腔MEC的生长。基于这些数据，Aim 3将研究潜在的 各种免疫细胞类型，特别是巨噬细胞（例如，M2-极化），在塑造p53- 管腔癌前区缺陷。总的来说，更好地了解激素的相互作用 环境和免疫细胞在乳腺与p53突变管腔MEC有助于发展 这种p53缺陷的癌前区域的研究有望导致乳腺癌预防的新策略， 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 这也可能对理解其他癌症类型的癌前病变具有广泛的意义。

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.