Translational Insights into Estrogen Receptor alpha-Positive Luminal Breast Cance

描述（由申请人提供）：我们已经开发了一种新的雌激素受体- α阳性(ER？STAT1-/-小鼠的+)乳腺癌表现出与ER？+人类腔内乳腺癌该模型的一个关键特征是，来自这些小鼠的原发肿瘤细胞的ER？和孕激素受体（PR），并表现出体外和体内雌激素生长依赖性。在基因表达谱的基础上，STAT1-/-小鼠的乳腺肿瘤细胞与人类腔内乳腺癌表现出惊人的相似性。在发育过程中，该模型也忠实地概括了人类腔内乳腺癌的自然历史，包括发展到卵巢激素独立的能力。因此，我们的模型填补了长期以来对最常见的人类乳腺癌的合适小鼠模型的需求。在这个u01应用中，我们建议利用这个模型来了解更多关于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。我们已经组建了一个多学科、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ER？从STAT1-/-小鼠的+（管腔）乳腺肿瘤中，特别强调定义在这些肿瘤细胞中起作用的高度激活的JAK2-STAT3/5信号通路的作用，以及鉴定ER？+乳腺肿瘤细胞表面，要么负责失调的JAK2-STAT3/5信号，要么可能用于靶向显像剂或治疗药物直接针对肿瘤。在具体目标2中，我们将定义ER？STAT1-/- ER中的表达/信号，JAK2-STAT3/5信号和基因表达？在荷瘤小鼠卵巢切除术后生长的+（腔内）乳腺肿瘤，并探索这种进展的潜在机制。在具体目标3中，我们将使用微正电子发射断层扫描（microPET）成像来识别内质网的重要功能变化。表达/功能，肿瘤细胞表面标志物的表达和ER的细胞代谢/增殖？卵巢切除术前后STAT1-/-小鼠+（腔内）乳腺肿瘤的检测，探讨微pet是否可以作为治疗效果的替代指标。最后，在Specific Aim 4中，我们将开发新的肿瘤靶向组合疗法来有效治疗小鼠自然产生和移植的小鼠ER？我们希望将我们的发现转化为人类乳腺癌的新疗法

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