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Use of a transgenic mouse model of ovarian hyperstimulation to identify therapeutic targets and mechanisms in hormone-induced mammary cancer.

机译：卵巢过度刺激转基因小鼠模型在荷尔蒙诱导的乳腺癌中鉴定治疗靶点和机制的用途。

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摘要

Epidemiological studies and clinical trials have revealed the critical impact that reproductive hormones have on breast cancer. The work described in this dissertation characterizes a transgenic mouse model, the LH-overexpressing mouse, which develops mammary gland hyperplasia and tumorigenesis in response to ovarian hyperstimulation, making it a unique model of hormone-induced mammary cancer. The hyperplasia in these mice is ovary-dependent and is due to a dramatic increase in proliferation of mammary epithelial cells. Most of the spontaneous mammary tumors that form in this model are mammary intraepithelial neoplasias that lack expression of both estrogen and progesterone receptors.; The LH-overexpressing mice have been utilized to investigate potential therapeutic targets and identify mechanisms that contribute to hormone-mediated mammary gland pathology. Similar to observations made in human breast cancer, the pre-neoplastic mammary glands and tumors of LH-overexpressing mice demonstrate increased expression of vitamin D receptor, supporting the notion that this protein is a potential target for therapy. Treatment with EB1089, a vitamin D receptor agonist, results in decreased proliferation in the pre-neoplastic mammary glands of LH-overexpressing mice and reduces the growth rate of a subset of established mammary tumors, providing evidence for both chemopreventive and chemotherapeutic benefits of activating the vitamin D receptor.; Analysis of pre-neoplastic mammary glands of LH-overexpressing mice has revealed the presence of centrosome amplification, suggesting that genomic instability may contribute to hormone-induced mammary tumorigenesis. Although centrosome amplification and genomic instability in human cancers are often associated with mutations in the p53 protein, the p53 sequence is intact in mammary tumors of LH-overexpressing mice. Furthermore, p53 is capable of being functionally activated in the mammary glands of transgenic mice in response to ionizing radiation, as evidenced by increased phosphorylation, upregulation of target genes, and induction of apoptosis. Along with the fact that introduction of a mutant form of p53 does not alter tumor latency, these data suggest that hormone-induced mammary tumors is not dependent on direct perturbation of the p53 signaling pathway. Future studies using the LH-overexpressing mouse should provide further insight into both potential therapeutic targets for treatment of hormone-induced mammary cancer and the mechanisms through which this disease progresses.
机译：流行病学研究和临床试验表明，生殖激素对乳腺癌具有至关重要的影响。本论文描述的工作表征了转基因小鼠模型，即过表达LH的小鼠，该小鼠在响应卵巢过度刺激后会发生乳腺增生和肿瘤发生，从而使其成为激素诱导的乳癌的独特模型。这些小鼠中的增生是卵巢依赖性的，并且是由于乳腺上皮细胞的增殖急剧增加所致。在该模型中形成的大多数自发性乳腺肿瘤是缺乏雌激素和孕激素受体表达的乳腺上皮内瘤变。过度表达LH的小鼠已被用于研究潜在的治疗靶标，并确定促成激素介导的乳腺病理的机制。与在人类乳腺癌中所做的观察相似，肿瘤前的乳腺和过表达LH的小鼠的肿瘤表现出维生素D受体表达的增加，支持这种蛋白质是潜在治疗靶点的观点。维生素D受体激动剂EB1089的治疗可导致过表达LH的小鼠的肿瘤前乳腺中的增殖减少，并降低一部分已确定的乳腺肿瘤的生长速度，从而为激活该药物的化学预防和化学治疗益处提供了证据维生素D受体。对过表达LH的小鼠的肿瘤前乳腺的分析揭示了中心体扩增的存在，这表明基因组不稳定性可能有助于激素诱导的乳腺肿瘤发生。尽管人类癌症中的中心体扩增和基因组不稳定性通常与p53蛋白的突变有关，但p53序列在过表达LH的小鼠乳腺肿瘤中是完整的。此外，p53能够响应于电离辐射而在转基因小鼠的乳腺中被功能性激活，如磷酸化增加，靶基因的上调和诱导细胞凋亡所证明的。除了引入p53突变形式不会改变肿瘤潜伏期外，这些数据还表明激素诱导的乳腺肿瘤不依赖于p53信号通路的直接扰动。使用过表达LH的小鼠进行的进一步研究应提供对激素诱导的乳癌治疗的潜在治疗靶标以及该疾病进展机制的进一步了解。

著录项

  • 作者

    Milliken, Erin Lee.;

  • 作者单位

    Case Western Reserve University.;

  • 授予单位 Case Western Reserve University.;
  • 学科 Health Sciences Pharmacology.; Biology Animal Physiology.; Biology Molecular.; Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 214 p.
  • 总页数 214
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;生理学;分子遗传学;肿瘤学;
  • 关键词

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