Translational Insights into Estrogen Receptor alpha-Positive Luminal Breast Cance

描述(申请人提供)：我们开发了一种新的雌激素受体α阳性(ER？+)乳腺癌小鼠模型，该模型在STAT1-/-小鼠中显示出与人类ER？+腔乳腺癌惊人的相似之处。这个模型的一个关键特征是，这些小鼠的原代肿瘤细胞--90%的ER？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。在基因表达谱的基础上，在STAT1/-小鼠中发展起来的乳腺肿瘤细胞与人类腔内乳腺癌显示出极大的相似性。在发展上，这个模型也忠实地概括了人类管腔乳腺癌的自然历史，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。在这一U01应用中，我们建议利用这一模型来更多地了解管腔乳腺癌的起源和发展，并开发可以移植到人类的新疗法。我们组建了一个多学科、多机构的研究团队，利用最先进的技术实现以下四个具体目标。在具体目标1中，我们将完成来自STAT1-/-小鼠的ER？+(腔)乳腺肿瘤的特征，特别强调确定在这些肿瘤细胞中操作的过度激活的JAK2-STAT3/5信号通路的作用(S)，以及在ER？+乳腺肿瘤细胞表面识别差异表达的蛋白质，这些蛋白质要么负责失调的JAK2-STAT3/5信号转导，要么可能被用于靶向显像剂或直接针对肿瘤的治疗。在具体目标2中，我们将定义ER中发生的变化？研究STAT1-/-ER？+(腔内)乳腺肿瘤在荷瘤小鼠卵巢切除后生长过程中的表达/信号转导、JAK2-STAT3/5信号转导和基因表达，并探讨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？研究卵巢切除前后STAT1+(腔)小鼠乳腺肿瘤的表达/功能、肿瘤细胞表面标志物的表达及细胞代谢/增殖情况，探讨microPET能否作为疗效的替代指标。最后，在特定目标4中，我们将开发新的肿瘤靶向组合疗法，有效地治疗自然产生和移植的小鼠ER？+(腔)乳腺癌，希望将我们的发现转化为治疗人类乳腺癌的新方法。

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