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Prolactin pathways and metastatic progression of ER-positive breast cancer

催乳素通路和 ER 阳性乳腺癌的转移进展

基本信息

批准号：
9178131
负责人：
HALLGEIR RUI
金额：
$ 36.29万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9178131
关键词：
Address Adoption Affect Agonist B-Cell Lymphoma 6 Protein BCL6 gene Basal Cell Biochemical Genetics Biological Markers Blood Circulation Breast Cancer Model Cattle Cell Line Clinical Clinical Management Clinical Trials Dependence Detection Development Disease Distant Distant Metastasis Endocrine Environment Estrogen Antagonists Estrogen Receptor 2 Estrogen Receptors Estrogen Therapy Estrogen receptor positive Estrogens Exhibits Experimental Models Failure GATA3 gene Genetic Engineering Goals Growth Health Hormones Human Human Activities IL2RA gene In Vitro Knock-in Mouse Laboratories Lead Liver Lung Mammary gland Metastatic Neoplasm to the Lung Metastatic breast cancer Modeling Molecular Monitor Mus Neoplasm Metastasis Newly Diagnosed Nucleic Acids Operative Surgical Procedures Outcome Pathway interactions Patients Physiological Population Pre-Clinical Model Prolactin Prolactin Receptor Proteins Refractory Refractory Disease Regulation Residual Tumors Resistance Risk Factors Role Selection Bias Serum Signal Transduction Site Staging Subgroup Testing Time Transcription Repressor/Corepressor Treatment Failure Undifferentiated Up-Regulation Work Xenograft procedure base cancer cell cancer subtypes candidate marker cohort expectation humanized mouse improved in vivo inhibitor/antagonist innovation insight malignant breast neoplasm mortality novel strategies pre-clinical preclinical study resistance mechanism response therapy resistant tool tumor

项目摘要

DESCRIPTION (provided by applicant): Estrogen receptor-� positive (ER�+) breast cancer (BC) represents 70-80% of newly diagnosed cases. While potentially responsive to anti-estrogens, progression of ER�+ BC to anti-estrogen refractory disease in the metastatic setting is a common occurrence. Endocrine resistance mechanisms may differ between subtypes of ER�+ BC and involve both ER�-independent and ER�-dependent forms that remain poorly understood. Prolactin (PRL) interacts with estrogens to stimulate growth of certain subtypes of ER�+ BC. At the same time, the PRL-Jak-Stat5 pathway promotes differentiation and inhibits invasive features of BC, and loss of Stat5a signaling in a subgroup of ER�+ BC is associated with anti-estrogen therapy failure. The involvement of PRL pathways in growth and progression of anti-estrogen refractory BC subtypes remains to be determined. There is a lack of preclinical human ER�+ BC models that recapitulate progression from localized mammary gland growth to distant metastasis. Xenografts of patient-derived ER�+ BC exhibit poor take rate in mice. We have discovered that murine PRL is a poor agonist and a potent antagonist for human PRL receptor (PRLr). Bovine PRL is also a poor agonist with antagonist activity for human PRLr. Laboratory human BC lines therefore have been selected for PRL-independent growth and may only represent subtype(s) of ER�+ BC. To address this problem, we generated hPRL knock-in mice in the immunodeficient Nod-Scid-IL2R? strain that express physiological levels of circulating hPRL. Remarkably, PRL-humanized mice display greatly increased take rate of patient-derived xenografts of ER�+ BC. We established a panel of serially transplantable ER�+ Luminal B lines, several of which spontaneously metastasize to lungs and liver. The distant metastases become anti-estrogen refractory despite continued expression of ER�, but show PRL-dependence. Our long-range goal is to determine mechanisms of anti-estrogen refractoriness of BC to improve clinical management. Aim 1 is focused on Luminobasal subtype of BC (ER�+/CK5+) and explores a distinct ER�-independent mechanism of anti-estrogen refractory BC recently recognized in pre-existing ER�+ laboratory cell lines. We hypothesize that in Luminobasal BC, loss of PRL-Stat5 signaling promotes loss of ER� and subsequent anti-estrogen resistance due to defective Stat5a-driven differentiation. Aims 2 and 3 are focused on the Luminal B BC subtype (ER�+/CK5-/Ki67high) and will use PRL-dependent patient-derived xenograft lines. Aim 2 will test the hypothesis that in Luminal B BC, unlike in Luminobasal BC, PRL facilitates growth and survival of metastases and that PRLr-pathway targeting cooperates with anti-estrogens to eliminate distant metastases. Aim 3 will explore novel strategies for detecting and monitoring latent residual disease.

描述（由申请人提供）：雌激素受体阳性（ER+）乳腺癌（BC）占新诊断病例的70-80%。虽然对抗雌激素有潜在的反应，但ER + BC在转移性环境中进展为抗雌激素难治性疾病是常见的。内分泌抵抗机制可能在ER + BC亚型之间存在差异，并且涉及ER非依赖性和ER依赖性形式，这些形式仍然知之甚少。催乳素（PRL）与雌激素相互作用，刺激某些亚型的ER + BC的生长。与此同时，PRL-Jak-Stat 5通路促进分化并抑制BC的侵袭性特征，ER β + BC亚组中Stat 5a信号转导的丧失与抗雌激素治疗失败有关。PRL通路参与抗雌激素难治性BC亚型的生长和进展仍有待确定。目前缺乏临床前人类ER + BC模型来概括从局部乳腺生长到远处转移的进展。患者来源的ER + BC的异种移植物在小鼠中表现出较差的移植率。我们已经发现，小鼠PRL是一个穷人的激动剂和有效的拮抗剂的人PRL受体（PRLr）。牛PRL也是一种对人PRL r具有拮抗活性的不良激动剂。因此，实验室人类BC系已被选择用于PRL非依赖性生长，并且可能仅代表ER + BC的亚型。为了解决这个问题，我们产生的hPRL基因敲入小鼠的免疫缺陷Nod-Scid-IL 2 R？表达生理水平循环hPRL菌株。值得注意的是，PRL人源化小鼠显示出患者来源的ER + BC异种移植物的摄取率大大增加。我们建立了一组可连续移植的ER β + Luminal B细胞系，其中几个自发转移到肺和肝。尽管ER β持续表达，但远处转移瘤成为抗雌激素难治性，但表现出PRL依赖性。我们的长期目标是确定抗雌激素难治性乳腺癌的机制，以改善临床管理。目的1是关注BC的Luminobasal亚型（ER +/CK 5+），并探索最近在已有的ER+实验室细胞系中发现的抗雌激素难治性BC的独特的ER-非依赖性机制。我们假设，在Luminobasal BC中，PRL-Stat 5信号传导的丧失促进了ER β的丧失，随后由于缺陷的Stat 5a驱动的分化而导致抗雌激素抵抗。目标2和3集中在管腔B BC亚型（ER β +/CK 5-/Ki 67高），并将使用PRL依赖性患者来源的异种移植物系。目的2将检验以下假设：与Luminobasal BC不同，在Luminal B BC中，PRL促进转移瘤的生长和存活，并且靶向PRL r途径与抗雌激素协同作用以消除远处转移瘤。目的3将探索新的策略，检测和监测潜在的残留疾病。