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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：
8888057
负责人：
HALLGEIR RUI
金额：
$ 37.31万
依托单位：
THOMAS JEFFERSON UNIVERSITY
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8888057
关键词：
Address Adoption Affect Agonist B-Cell Lymphoma 6 Protein BCL6 gene Basal Cell Biochemical Genetics Breast Cancer Model Cattle Cell Line Clinical Clinical Management Clinical Trials Dependence 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 transcription factor Genetic Engineering Goals Growth Hormones Human Human Activities In Vitro Investigation Knock-in Mouse Laboratories Lead Liver Lung Mammary gland Modeling Molecular Monitor Mus Neoplasm Metastasis Newly Diagnosed Outcome Pathway interactions Patients Physiological Population Pre-Clinical Model Prolactin Prolactin Receptor Proteins Refractory Refractory Disease Regulation Resistance Risk Factors Role Selection Bias Serum Signal Transduction Site Subgroup Testing Time Transcription Repressor/Corepressor Tumor Markers Undifferentiated Up-Regulation Work Xenograft procedure base breast cancer diagnosis cohort expectation improved in vivo inhibitor/antagonist innovation insight malignant breast neoplasm mortality novel novel strategies oncology pre-clinical preclinical study public health relevance resistance mechanism response therapy resistant tool tumor

项目摘要

DESCRIPTION (provided by applicant): Estrogen receptor-a positive (ERα+) breast cancer (BC) represents 70-80% of newly diagnosed cases. While potentially responsive to anti-estrogens, progression of ERα+ BC to anti-estrogen refractory disease in the metastatic setting is a common occurrence. Endocrine resistance mechanisms may differ between subtypes of ERα+ BC and involve both ERα-independent and ERα-dependent forms that remain poorly understood. Prolactin (PRL) interacts with estrogens to stimulate growth of certain subtypes of ERα+ 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 ERα+ 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 ERα+ BC models that recapitulate progression from localized mammary gland growth to distant metastasis. Xenografts of patient-derived ERα+ 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 ERα+ BC. To address this problem, we generated hPRL knock-in mice in the immunodeficient Nod-Scid-IL2Rγ strain that express physiological levels of circulating hPRL. Remarkably, PRL-humanized mice display greatly increased take rate of patient-derived xenografts of ERα+ BC. We established a novel panel of serially transplantable ERα+ Luminal B BC lines, several of which spontaneously metastasize to lungs and liver. The distant metastases become anti-estrogen refractory despite continued expression of ERα+, 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 a recently identified Luminobasal subtype of ERα+ BC (ERα+/CK5+). Aim 1 explores a distinct ERα-independent mechanism of anti-estrogen refractory BC in pre-existing ERα+ laboratory cell lines. We hypothesize that in Luminobasal BC, loss of PRL-Stat5 signaling promotes loss of ERα and subsequent anti-estrogen resistance due to defective Stat5a-driven differentiation. Aim 2 is focused on the Luminal B BC subtype (ERα+/CK5-/Ki67high) and is centered on our new 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.

描述(申请人提供)：雌激素受体-a阳性(ERα+)乳腺癌(BC)占新诊断病例的70%-80%。虽然ERα+BC对抗雌激素有潜在的反应，但在转移环境中进展为抗雌激素难治性疾病是一种常见的情况。内分泌耐药机制可能因ERα+BC亚型不同而不同，涉及ERα非依赖性和ERα依赖性两种形式，目前仍知之甚少。催乳素(PRL)与雌激素相互作用，刺激某些ERα+BC亚型的生长。同时，PRL-JAK-STAT5通路促进了BC的分化，抑制了BC的侵袭特性，ERα+BC亚群中STAT5a信号的缺失与抗雌激素治疗失败有关。PRL通路在抗雌激素耐药BC亚型的生长和进展中的作用仍有待确定。缺乏临床前人类ER、α+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ERα+BC的异种移植在小鼠中的接种率很低。我们发现，小鼠催乳素是人催乳素受体(PRLr)的弱激动剂和强有力的拮抗剂。牛催乳素对人催乳素受体的拮抗活性也较差。因此，实验室人BC系已被选择用于非催乳素依赖生长，并且可能仅代表ERα+BC亚型(S)。为了解决这个问题，我们在免疫缺陷的NOD-SCID-IL2Rγ株中产生了hPRL敲入小鼠，表达生理水平的循环hPRL。值得注意的是，PRL人源化小鼠显著提高了患者来源的ERα+BC异种移植物的接种率。我们建立了一组新的可连续移植的ERα+腔B BC细胞系，其中几株会自发转移到肺和肝脏。尽管ERα+持续表达，但远处转移的肿瘤对雌激素不敏感，但表现为催乳素依赖。我们的长期目标是确定BC的抗雌激素耐药机制，以改善临床治疗。目的1研究新近发现的ERα+BC亚型(ERα+/CK5+)。目的1在已有的ERα+实验细胞系中探索ERα非依赖性的抗雌激素耐药BC的机制。我们假设，在发光性基底BC中，PRL-STAT5信号的丢失促进了ERα的丢失，以及随后由于STAT5a驱动的缺陷分化而产生的抗雌激素抵抗。AIM 2专注于腔B BC亚型(ERα+/CK5-/Ki67High)，并以我们新的PRL依赖患者来源的异种移植株为中心。目的2将验证这一假设，即在腔内B BC，不同于在光基底BC，PRL促进转移的生长和生存，并且PRLr通路靶向与抗雌激素协同作用以消除远处转移。