Translational Insights into Estrogen Receptor alpha-Positive Luminal Breast Cance

雌激素受体α阳性管腔乳腺癌的转化见解

• 批准号: 7916528
• 负责人: Robert D Cardiff
• 金额: $ 82.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-17 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916528
• 关键词: Arts; Biological; Breast; Breast Cancer Model; Cell surface; Cellular biology; Characteristics; Dependency; Development; Employee Strikes; Engraftment; Estrogen Receptor alpha; Estrogens; Event; Evolution; Gene Expression; Gene Expression Profiling; Goals; Growth; Human; Image; In Vitro; Learning; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Metabolism; Modeling; Molecular; Molecular Genetics; Mus; Natural History; Ovarian; Ovarian hormone; Ovariectomy; Positron-Emission Tomography; Primary Neoplasm; Progesterone Receptors; Proteins; Research; Role; STAT1 gene; Signal Pathway; Signal Transduction; Surrogate Markers; Technology; Therapeutic; Translating; Transplantation; Treatment Efficacy; Variant; base; combinatorial; in vivo; insight; malignant breast neoplasm; mouse model; neoplastic cell; novel; prevent; tumor

DESCRIPTION (provided by applicant): We have developed a novel mouse model of estrogen receptor-alpha positive (ER?+) mammary cancer in STAT1-/- mice that shows remarkable resemblance to ER?+ luminal breast cancer in humans. A key feature of this model is that primary tumor cells from these mice- are >90% positive for ER? and progesterone receptors (PR) and show estrogen growth dependency in vitro and in vivo. On the basis of gene expression profiling, the mammary tumor cells that develop in STAT1-/- mice show extraordinary similarity to human luminal breast cancers. Developmentally this model also faithfully recapitulates the natural history of human luminal breast cancer, including the capacity to progress to ovarian hormone independence. Thus, our model fills a long-standing need for a suitable mouse model of the most common form of human breast cancer. In this U0l application, we propose to capitalize on this model to learn more about the origins and progression of luminal breast cancers, and to develop novel therapies that can be translated to humans. We have assembled a multi-disciplinary, multi-institutional research team to pursue the following four Specific Aims using state-of-the-art technologies. In Specific Aim 1 we will complete the characterization of ER?+ (luminal) mammary tumors from STAT1-/- mice, placing special emphasis on defining the role(s) of the hyperactivated JAK2-STAT3/5 signaling pathway that is operative in these tumor cells, and in identifying differentially expressed proteins on ER?+ mammary tumor cell surfaces that are either responsible for the dysregulated JAK2-STAT3/5 signaling or might be used to target imaging agents or therapeutics directly to the tumor. In Specific Aim 2 we will define the changes that occur in ER? expression/signaling, JAK2-STAT3/5 signaling and gene expression in STAT1-/- ER?+ (luminal) mammary tumors that grow out following ovariectomy of tumor bearing mice, and explore the underlying mechanisms for this progression. In Specific Aim 3 we will use micro-positron emission tomography (microPET) imaging to identify functionally important changes in ER? expression/function, expression of tumor cell surface markers and cellular metabolism/proliferation of ER?+ (luminal) mammary tumors in STAT1-/- mice before and after ovariectomy, and explore whether microPET can be used as a surrogate marker of therapeutic efficacy. Finally, in Specific Aim 4 we will develop novel combinatorial tumor-targeted therapies to effectively treat mice bearing naturally arising and transplanted mouse ER?+ (luminal) mammary cancers with the hope of translating our findings into new treatments for human breast cancer

描述（由申请人提供）：我们在STAT1-/-小鼠中开发了一种新的雌激素受体-α阳性（ER？+）乳腺癌小鼠模型，该模型与人类的ER？+管腔乳腺癌非常相似。该模型的一个关键特征是来自这些小鼠的原发性肿瘤细胞的 ER 阳性率 >90%？和孕激素受体（PR），并在体外和体内表现出雌激素生长依赖性。根据基因表达谱，STAT1-/-小鼠中发育的乳腺肿瘤细胞与人类管腔乳腺癌非常相似。从发育角度来看，该模型还忠实地再现了人类腔内乳腺癌的自然史，包括进展为卵巢激素独立的能力。因此，我们的模型满足了对人类乳腺癌最常见形式的合适小鼠模型的长期需求。在这个 U0l 应用中，我们建议利用这个模型来更多地了解腔内乳腺癌的起源和进展，并开发可以转化为人类的新疗法。我们组建了一支多学科、多机构的研究团队，利用最先进的技术来实现以下四个具体目标。在具体目标 1 中，我们将完成 STAT1-/- 小鼠 ER?+（管腔）乳腺肿瘤的表征，特别强调定义在这些肿瘤中起作用的过度激活的 JAK2-STAT3/5 信号通路的作用。肿瘤细胞，并鉴定 ER?+ 乳腺肿瘤细胞表面的差异表达蛋白，这些蛋白要么导致 JAK2-STAT3/5 信号传导失调，要么可用于将显像剂或治疗剂直接靶向肿瘤细胞。肿瘤。在具体目标 2 中，我们将定义 ER 中发生的变化？研究人员对荷瘤小鼠卵巢切除后生长的 STAT1-/- ER?+（管腔）乳腺肿瘤中的表达/信号传导、JAK2-STAT3/5 信号传导和基因表达进行了研究，并探讨了这一进展的潜在机制。在具体目标 3 中，我们将使用微正电子发射断层扫描 (microPET) 成像来识别 ER 中功能上重要的变化？探讨 STAT1-/- 小鼠卵巢切除前后 ER?+ (luminal) 乳腺肿瘤的表达/功能、肿瘤细胞表面标志物的表达和细胞代谢/增殖，并探讨 microPET 是否可以作为治疗效果的替代标志物。最后，在具体目标 4 中，我们将开发新型组合肿瘤靶向疗法，以有效治疗自然产生和移植的小鼠 ER?+（管腔）乳腺癌的小鼠，希望将我们的发现转化为人类乳腺癌的新疗法